PT788498E - ANTIMICROBIAL COMPOUNDS OF PHENYLXAZOLIDINONE - Google Patents

Abstract

A compound of structural formula (I), or pharmaceutically acceptable salts thereof wherein: Q is selected from the structures i, ii, iii, iv and v. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly aerobic gram-positive bacteria, including multiply-resistant staphylococci, enterococci and streptococci, as well as anaerobic organisms such as bacteroids and clostridia species, and acid-fast bacteria such as as Mycobacterium tuberculosis and other mycobacterial species.

Description

ΕΡ Ο 788 498 / ΡΤ

Description "Phenyloxazolidinone antimicrobial compounds"

Background of the Invention The present invention discloses novel and useful phenyloxazolidinone compounds having a pyrrolidinyl or azetidinyl moiety. The compounds are useful antimicrobial agents effective against various human and veterinary pathogens, including aerobic gram-positive bacteria such as staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp., and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.

Disclosure of Information

The present compounds are related, by their structure of the phenyloxazolidinone ring, to the compounds disclosed in the publications below except that the present compounds have a multi-substituted pyrrolidinyl or azetidinyl moiety. The present compounds are unique and have useful antibacterial activity. PCT / US93 / 03570 discloses oxazolidinones containing a substituted diazine moiety and their uses as antimicrobial agents. PCT / US92 / 08267 discloses substituted aryl and heteroaryl-phenyloxazolidinones useful as antibacterial agents. PCT / US89 / 03548 discloses 5'indolidinyl-5β-amidomethyloxazolidinones, 3-phenyl (substituted in the fused ring) -5β-amidomethyloxazolidinones and 3-phenyl (substituted with nitrogen) -5β-amidomethyloxazolidinones which are useful as antibacterial agents.

Other references disclosing various oxazolidinones include U.S. Patent 4,801,600, 4,921,869, Gregory W.A., et al., J. Med. Chem. 32, 1673-81 (1989); Gregory W.A., et al., J. Med. Chem. 33, 2569-78 (1990); Wang C., et al., Tetrahedron. 45, 1323-26 (1989); and Brittelli, et al., J. Med. Chem. 35, 1156 (1992). 87 111 ΕΡ Ο 788 498 / ΡΤ 2

European Patent Publication 352 781 discloses phenyloxazolidinones substituted with phenyl and pyridyl. European Patent Publication 316,594 discloses 3-substituted styryloxazolidinones. European Patent Publication 312 000 discloses phenylmethyl and pyridinylmethyl substituted phenyloxazolidinones.

Summary of the Invention

In one aspect the present invention is a compound of Formula I:

Q

or pharmaceutically acceptable salts thereof, in which:

Q is selected from structures i, ii, iii, iv and v:

(b)

(A) H or F, (b) OR7,

(F) NR8 R9, (e) CN, (f) C1 -C4 alkoxycarbonyl, (g) carboxamide, (h) C1 -C4 acyl optionally substituted with one or more of fluorine, hydroxy, C1 -C4 alkoxy, C1 -C4 acyloxy; (i) NHO (C1 -C6 alkyl) or NHOCH2 Ph (O) NS02 R where R is alkyl optionally substituted with one or more F, Cl, alkoxy or phenyl; each of R2 is independently selected from the others from (a) H or F, (b) OH, (c) OR where R is C1 -C6 alkyl, (d) alkyl (e) Ph; each of R3 is independently selected from the others from (a) H, (b) C1 -C3 alkyl which may be optionally substituted with F, Cl, hydroxy, C1 -C4 alkoxycarbonyl, C1 -C3 acyloxy, C1 -C3 alkyloxy or N (C1 -C4 alkyl) 2 , (c) phenyl, (d) pyridyl; R4 are independently H, OCH3, F or Cl; R5 is (a) hydrogen, (b) C1 -C8 alkyl which may be optionally substituted with one or more of the following: F, Cl, hydroxy, C1 -C8 alkoxy, C1 -C8 acyloxy, (c) C3 -C6 cycloalkyl, (d) amino, ( e) C1 -C8 alkylamino, (f) C1 -C8 alkoxyamino, (g) C1 -C8 alkoxy; R6 is (a) O, (b) S, (c) NR10, (d) CR11R12,

Wherein R = C 1 -C 6 alkyl, (f) O (CH 2) m O, (g) (SR) 2, wherein R = C 1 -C 6 alkyl, (h) S CH2) mS, (i) to fill the valence OH and Η, H and Η, H and F or F and F; R7 is (a) H, (b) C1 -C8 alkyl optionally substituted with one or more of the following: F, Cl, -CN, hydroxy, C1 -C8 alkoxy, C1 -C8 acyloxy, C1 -C8 alkoxycarbonyl, phenyl, (c) C1 -C8 acyl optionally substituted with one or more of the following: hydroxy, C 1 -C 8 alkoxy, C 1 -C 6 acyloxy, (d) C 1 -C 6 alkoxycarbonyl, (e) carboxamide, optionally substituted with C 1 -C 4 alkyl or phenyl on the carboxamide nitrogen, ) phenyl, optionally substituted with one or more of the following: halogen, CN, C1 -C3 alkoxy, C1 -C3 alkoxycarbonyl, C1 -C4 alkyl, optionally substituted with one or more of F or C1 -C3 alkoxy; R8 and R9 are independently selected from: (a) H, (b) C1 -C8 alkyl optionally substituted with one or more of the following: F, Cl, -CN, hydroxy, C1 -C6 alkoxy, C1 -C8 acyloxy, C1-6 alkoxycarbonyl (C) C1 -C8 acyl optionally substituted with one or more of the following: hydroxy, C1 -C8 alkoxy, C1 -C8 acyloxy, amino, C1 -C4 acylamino, aminoC1-4 acylamino (d) benzoyl optionally substituted with one or more of the following: F, Cl, hydroxy, C1 -C6 alkoxy, C1 -C6 acyloxy, amino, C1 -C4 acylamino, C1 -C4 alkoxycarbonylamino, (e) C1 -C8 alkoxycarbonyl, benzyloxycarbonyl, tert.butoxycarbonyl, f) carboxamide, optionally substituted with a C1 -C6 alkyl, or phenyl on the carboxamide nitrogen, (g) trifluoroacetyl, (h) CO (C1 -C6 alkyl); 87 111 ΕΡ Ο 788 498 / ΡΤ 5

R10 is (a) Η, (b) OR7, (c) NHR ', (d) C1 -C8 alkyl optionally substituted with phenyl; R11 and R12 are independently selected from: (a) H. F, (b) C1 -C4 alkyl optionally substituted with halogen. hydroxy, C1 -C4 alkoxy, C1 -C4 alkoxycarbonyl, phenyl, (c) C1 -C8 acyl, (d) C1 -C4 alkoxycarbonyl, (e) CN; R17 is (a) O, (b) S; R18 and R19 are independently selected from: (a) H, (b) C1 -C4 alkyl optionally substituted with halogen, hydroxy, C1 -C4 alkoxy, (c) OH, (d) C1 -C4 alkoxy, C4 alkyl optionally substituted with hydroxy or C1-4 alkoxy, (e) NR8 R9, (f) -OC (O) C1-4 alkyl; R20 is (a) H, (b) CH3; n is 0 or 1 and m is 2 or 3.

In one aspect the present invention is a compound of Formula I:

H 6 87 111 ΕΡ Ο 788 498 / ΡΤ

In another aspect the present invention is composed of Structural Formula II:

In another aspect the present invention is composed of Structural Formula iii:

87 111 ΕΡ Ο 788 498 / ΡΤ 7

In yet another aspect the present invention is a compound of Formula IV:

In yet another aspect the present invention is a compound of Formula v:

In another aspect, the present invention is directed to a method for treating microbial infections in humans or other warm-blooded animals upon administration to a patient in need thereof of an effective amount of a compound of Formula I ( iv) described above. The compound can be administered in a pharmaceutical composition either oral, parenterally or topically. Preferably, the compound is administered in an amount of from about 0.1 to about 100 mg / kg body weight / day, more preferably from about 3.0 to about 50 mg / kg body weight / day.

Detailed Description of the Invention The present invention discloses novel substituted azetidinyl and pyrrolidinylphenyloxazolidinones of Structural Formula I (and as structurally depicted in Formulas i-v) as described above. The compounds are useful antimicrobial agents effective against various human and veterinary pathogens, particularly aerobic gram-positive bacteria including staphylococci, enterococci and multiresistant streptococci as well as anaerobic organisms such as bacteroid species and clostridia, and acid resistant bacteria such as Mycobacterium tuberculosis and other mycobacterial species.

The substituents R4 are both preferably fluorine and more preferably fluorine and hydrogen. The substituent R 5 is preferably hydrogen, methyl, dichloromethyl, hydroxymethyl or methoxy. More preferably R 5 is hydrogen, methoxy or methyl. It is preferred that R 5 is methyl. The substituent R6 is preferably O, OCH2 CH2 O, NOH and NOCH3. "Alkyl" means chains of carbon atoms having the desired number of carbon atoms, which may be straight chain or branched. "Alkoxy" means the number of carbon atoms desired attached to an oxygen forming groups such as methoxy (-OCH 3), ethyloxy, butyloxy, etc. and their isomeric forms. "Acyloxy" means the number of carbon atoms desired to form an organic acid in which the OH group has been removed, such as acetyl, CH 3 CO-; benzoyl, C 6 H 5 CO-.

In the preferred embodiment of the invention,

"Cycloalkyl" means the number of carbon atoms intended to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. and their isomeric forms. "Ph" means phenyl. "Carbonyl" is a -C (= O) - moiety. "Amino" means an NH 2, "alkylamino" is when one of the hydrogen positions is replaced by an alkyl, and "dialkylamino" is when both the hydrogen are replaced by an alkyl group. "Pharmaceutically acceptable salts" are acid addition salts which may be prepared by any means recognized in the art. Typically, acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, malate, succinate, tartrate, cyclohexanesulfamates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, fumarates and other counter- ions to pharmaceutically acceptable amines.

Azetidinyl-Phenyloxazolidinones: The preferred C-5 absolute configuration of the oxazolidinone ring of the compounds claimed in this invention is that represented in the structures of Formula i and ii. This absolute configuration is called (S) according to the Cahn-Ingold-Prelog nomenclature system. It is this (S) -enantiomer which is pharmacologically active as an antibacterial agent. The racemic mixture is useful in the same way and for the same purpose as the pure (S) enantiomer; the difference is that twice as much racemic mixing material has to be used to produce the same antibacterial effect. It will be apparent to one skilled in the art that when a chiral center (R other than H) is present in the azetidine moiety of the compounds of Formula I, ii, and iii, then diastereomers are possible. These diastereomers, in racemic and enantiomerically enriched forms, are also within the scope of the compounds of Formula i, ii, and iii of the invention. The preferred preparation method of the oxazolidinones of Formula I, ii, and iii in the enantiomerically pure form is shown in Schemes 1-VI. Schemes 1-VI contain the generic structural representations for the preparation of the various compounds of the invention centered around the cyclic structure of the nucleus wherein Q is i, ii, or iii.

87 111 ΕΡ Ο 788 498 / ΡΤ 10

As shown in Scheme I, the 3-hydroxyazetidines of structure I may be deprotonated with a suitable base, for example sodium hydride, in a suitable solvent, for example tetrahydrofuran (THF), and then alkylated with alkyl halides, for example methyl iodide to give azetidine ethers 2 (R 13 = alkyl). If desired, the aryl azetidine 2 (R 13 = optionally substituted phenyl) ethers can be prepared from azetidinol 1 using known procedures (Taylor, CR, Jr .; Cal, AD, Jr .; Stauffer, HF, Jr., Patents US 4 956 359, 1990) The benzhydryl group of 1 and 2 is removed by hydrogenolysis in the presence of an inorganic acid, for example hydrochloric acid, and in the presence of a suitable catalyst, for example palladium hydroxide on carbon, in a suitable solvent, such as methanol, to give the azetidines 3 (R 13 = H, alkyl, phenyl). The compounds of structure 3 are then reacted with a functionalized nitrobenzene 4 (X = halogen or trifluoromethanesulfonate) in the presence of a suitable base / solvent combination, for example potassium phosphate dibasic in dimethylsulfoxide or Ν, Ν-diisopropylethylamine in acetonitrile or THF , and at a suitable temperature, typically from room temperature to 70øC, to give the adduct 5. If it is desired that R1 of a compound of Formula I or an advanced intermediate thereof is hydroxy, then a suitable protecting group, such as a tert-butyldimethylsilyl moiety, by reacting 5 (R 13 = H) with tert-butyldimethylsilyl chloride in the presence of imidazole in a suitable solvent such as δ-dimethylformamide (DMF) at room temperature to afford 5- (R 13 = tert- butyldimethylsilyl). It will be apparent to one skilled in the art that this protecting group is merely representative and that alternative protecting groups, as described in Greene, T. W .; Wuts, P.G. M. " Protective Groups in Organic Synthesis ", 2nd ed .; John Wiley &Sons; New York, 1991. The nitro group of 5 is then reduced by catalytic hydrogenation in the presence of a suitable catalyst, such as 10% palladium / carbon or Raney W-2 nickel, and in a suitable solvent, for example THF / H2O. When this latter solvent system is used, the reaction mixture is first filtered to remove the catalyst and the filtrate containing the aniline intermediate is then treated with, for example, sodium bicarbonate or benzyl or methyl chloroformate to give the corresponding benzyl derivatives (R 14 The urethanes 6 are then deprotonated with a suitable base such as n-butyllithium (n-BuLi), lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide in a suitable solvent such as n-butyllithium. solvent such as tetrahydrofuran (THF) and at a suitable temperature such as -78 to -40øC to give a lithiated intermediate which is then treated with (-) - (R) -glycidyl butyrate. Heating to room temperature then gives

Directly to the 5- (hydroxymethyl) oxazolidinones 7 in enantiomerically enriched form.

As shown in Scheme II, compound 7 is then converted to the corresponding mesylate 8 (R 15 = methyl) or arylsulfonate 8 (R 15 = ArSO 2, for example p-toluenesulfonyl) by the action of, for example, methanesulfonyl chloride / pyridine or chloride methanesulfonyl chloride / triethylamine / dichloromethane or p-toluenesulfonyl chloride / pyridine. The resulting sulfonate derivative 8 is then reacted with an azide source such as sodium or potassium azide in an aprotic solvent such as Ν, Ν-dimethylformamide (DMF) or 1-methyl-2-pyrrolidinone optionally in the presence of a catalyst such as as 18-crown-6 at a temperature of 50-90 ° C to give the azide 9. The azide is then reduced by hydrogenation with palladium on carbon or a platinum catalyst in a suitable solvent such as ethyl acetate or methanol to give corresponding amine 10. Alternatively, azide 9 may be reduced by treatment with a trivalent phosphorus compound such as triphenylphosphine in a suitable solvent such as tetrahydrofuran followed by addition of water. The intermediate amine 10 may also be prepared by treatment of the phthalimide derivative 11 (obtained by reacting sulfonate 8 with potassium phthalimide in a suitable solvent, for example acetonitrile at reflux temperature) with methylamine in ethanol / H2 O at reflux temperature. Alternatively, the amine 10 may be prepared directly from the mesylate 8 by ammonolysis with aqueous ammonium hydroxide in a solvent system consisting of H2 O / isopropanol / THF in a sealed reaction vessel immersed in an oil bath at 70-95 ° C. The amine 10 is then acylated by reactions known to those skilled in the art to give oxazolidinones of structure 12. For example, the amine may be reacted with an acid chloride or anhydride in a basic solvent such as pyridine at a temperature ranging from -30 to 30 ° C to give the acylated compound 12 (R 5 = optionally substituted alkyl). It will be apparent to one skilled in the art that other carbonyl groups within the scope of this invention may be readily appended to the amine by standard acylation techniques, for example those as outlined in March, J. Advanced Organic Chemistry, 3rd Ed .; John Wiley &Sons; New York, 1985; pag. 370-375, to give additional examples of 12. If it is desired that R 13 is H, then the tert -butyldimethylsilyl protecting group attached to the examples selected from 12 is removed employing appropriate conditions such as those set forth in Greene, T.W .; Wuts, P.G. M. " Protective Groups in Organic Synthesis ", 2nd ed .; John Wiley &Sons; New York, 1991, especially aqueous hydrofluoric acid in acetonitrile at 87 111 ΕΡ Ο 788 498 / ΡΤ 12

at room temperature, to give the corresponding alcohol. Compounds of structure 12 (R 13 = H, alkyl, optionally substituted phenyl) represent examples of azetidine substituted oxazolidinone antibacterial agents of Formula I, which are the subject of this invention.

The oxazolidinones containing azetidine 12, themselves examples of antibacterial agents of Formula I, may further be processed into additional compounds of Formula I and also examples of Structural Formula II as shown in Scheme III. For example, 12 (R13 = H) may be oxidized to the corresponding azetidinone 13 by reacting it with catalytic tetra-n-propylammonium perruthenate in the presence of N-methylmorpholine N-oxide and molecular sieves in acetonitrile / dichloromethane. Compound 13 is an example of an antibacterial agent of Formula II. The ketone moiety of 13 is susceptible to further modification. Reaction of 13 with Lawesson's reagent or alternative reagents, as described in March, J. " Advanced Organic Chemistry ", 4th ed .; John Wiley &Sons; New York, 1992; pag. 893-894, gives the corresponding thioketone 14 (R6 = S). Oximes 14 (for example, R 6 = NOH and NOCH 3) are readily prepared by reacting with, for example, hydroxylamine hydrochloride or methoxylamine hydrochloride in the presence of a suitable base, such as pyridine, in a suitable solvent, for example methanol, at room temperature. Various hydrazone derivatives (R6 = NNHR7) may be prepared by reacting 13 with hydrazines as described in Greene, T.W .; Wuts, P.G. M. " Protective Groups in Organic Synthesis ", 2nd ed .; John Wiley &Sons; New York, 1991, p. 212-213 and March, J. " Advanced Organic Chemistry ", 4th ed .; John Wiley &Sons; New York, 1992; pag. 904-905. Imines 14 (R6 = N-alkyl or N-aryl) are synthesized by treating 13 with primary amines, as described in March, J. " Advanced Organic Chemistry ", 4th ed .; John Wiley &Sons; New York, 1992; pag. 896-897. Olefinic derivatives (14: R6 = CR11 R12) are prepared by reacting 13 with various olefinating reagents, such as phosphorus ylides and the like, which are known to the person skilled in the art. Representative examples are described in March, J. " Advanced Organic Chemistry ", 4th ed .; John Wiley &Sons; New York, 1992; pag. 956-963. For the case where R 6 is CF 2 this would involve treatment of the ketone 13 with (Na 2 CO 2 F 2 Cl) sodium difluorochloroacetate and triphenylphosphate as described in Tetrahedron Letters 1964, p. 1461. The resulting olefinic bond may be reduced by catalytic hydrogenation or other methods known to the skilled person to provide examples of Structural Formula i. Other compounds of structure 14, for example cyclic and

May be prepared by reacting compound 13 with diols, dithiols, alcohols or thiols under conditions, for example, described in Greene, T. W .; Wuts, P. G. M. " Protective Groups in Organic Synthesis, 2nd ed .; John Wiley &Sons; New York, 1991, p. 177-207. Compound 12 (R13 = H) may also be converted into various derivatives (R16 = alkoxycarbonyl, carboxamide, optionally substituted acyl, etc.) by treating 12 with various carbonyl derivatives such as anhydrides, alkyl chloroformates, isocyanates and the like , in the presence of appropriate bases and in suitable solvents known to the person skilled in the art. Compounds 14 and 15 represent examples of oxazolidinone antibacterial agents of Formula I and ii.

Schemes IV-VI outline procedures for preparing examples of Structural Formula i wherein R 1 is a group other than OR 7. As shown in Scheme IV, mesylate 16, obtained by reacting the azetidinol 1 starting material with methanesulfonyl chloride in the presence of triethylamine and dichloromethane, is reacted with a variety of nucleophiles. For example, treatment of 16 with ammonia, primary amines or secondary amines gives 3-aminoazetidines of structure 17. Similarly, the treatment of 16 with thiolates or cyanide provides the adducts 18 and 19, respectively. Compound 19 may be reduced with lithium aluminum hydride and the like to give the corresponding 3- (aminomethyl) azetidine. Compound 19 may also be converted to the carboxylate derivative 21. Those skilled in the art may additionally transform the carboxylate moiety of 21 to the corresponding carboxamide or various acyl groups which upon further processing comprise further examples of antibacterial agents of Formula I. Compounds 17 and 20 may further be N-alkylated by procedures known to a person skilled in the art, including treatment of 17 and 20 with alkyl halides or tosylates in the presence of a suitable base. Alternatively, they may be nitrogen-joined to 17 and 20 alkyl groups selected by a reductive alkylation procedure as described in March, J. " Advanced Organic Chemistry ", 4th ed .; John Wiley &Sons; New York, 1992; pag. 898-900. In the case of the amino intermediates 17 and 20, when a free NH is present, it is necessary to protect these portions to allow some subsequent reactions to proceed without problems. The amino group can be converted into the corresponding t-butylcarbamate (BOC), benzylcarbamate (Cbz), trifluoroacetamide, or phthalimide derivatives and the like, as required, using procedures described in Greene, T.W .; Wuts, P.G. M. " Protective Groups in Organic Synthesis ", 2nd. ed .; John Wiley &Sons; New York, 14 87 111 ΕΡ Ο 788 498 / ΡΤ 1991, p. 309-403. The benzhydryl protecting group of 17-21 is then removed by hydrogenolysis in the presence of a suitable catalyst, for example palladium hydroxide on carbon and in the presence of an inorganic acid, for example hydrochloric acid, to give the intermediate azetidines (R1 different from OR '). Scheme V outlines the processing of intermediate azetidines 22 in examples of Structural Formula i (R1 other than OR7). The chemistry is essentially identical to that described in Scheme I. Compound 22 is initially converted to the nitrobenzene derivative 23. Reduction and conversion to carbamates of structure 24 is performed as described above. As described in Scheme I, intermediate 24 is processed into the optically active 5- (hydroxymethyl) oxazolidinone. Application of the procedures outlined in Scheme II then allows the conversion of 25 into compounds of structure 26. Removal of any appended protecting groups, for example BOC groups in compounds where R1 is amino, is achieved by methods known to the person skilled in the art for example those described in Greene, TW; Wuts, P.G. M. " Protective Groups in Organic Synthesis ", 2nd. ed .; John Wiley & Sons: New York, 1991. The resulting free amino group may then be N-alkylated or N-acylated, if desired, to give additional compounds of structure 26, which are examples of oxazolidinone antibacterial agents of Structural Formula i. Scheme VI shows a variation of the chemistry delineated in Scheme IV wherein the hydroxyazetidinylphenyloxazolidinone intermediate 12 (R13 = OH) is converted to the corresponding mesylate 27 by the action of methanesulfonyl chloride in the presence of a suitable base, such as triethylamine, and in an appropriate solvent, for example dichloromethane. The same nucleophilic shifts described in Scheme IV for mesylate 16 can be performed on the more functionalized mesylate 27 to give compounds 28-30. Employing procedures similar to those described in Scheme IV, 30 can be converted into compounds 31 and 32. Compounds 28-32 are examples of oxazolidinone antibacterial agents of Formula I, which are the subject of the invention. It will be apparent to one skilled in the art that compounds 28-32 are merely representative examples and are themselves amenable to further chemical modification to provide additional examples of Structural Formula i. Scheme VII outlines procedures for preparing compounds of Formula III. The 2-azetidinones of structure 33 are treated with a suitable base, for example sodium hydride, in a suitable solvent, for example THF, to give a deprotonated intermediate which is then reacted with a derivative nitrobenzene 4 (X = halogen) to provide adduct 34. It will be apparent to one skilled in the art that suitable protecting groups are required, for example those described in Greene, TW, Wuts, PGM " Protective Groups in Organic Synthesis ", 2a . ed .; John Wiley & Sounds: New York, 1991, for the selected substituents R18 and R19 of compound 33. Intermediate 34 can be converted through the steps outlined in Schemes I and II into compounds of structure 35, themselves examples of Structural Formula iii, which are the object of the invention. Alternatively, the azetidinyl substituted intermediate 36, prepared by procedures outlined in Schemes I and II, is oxidized to the corresponding azetidinone 35 (R17 = O) with, for example, catalytic ruthenium tetroxide in the presence of a suitable oxidizer, such as sodium metaperiodate and in a suitable solvent system, for example ethyl acetate / water. To prepare examples of compound 35 where R17 is S, the selected azetidinone intermediates are reacted with Lawesson's reagent or the like.

Examples of azetidinyl-phenyloxazolidinones which may be prepared as part of the invention are the following: 1. (S) -N - [[3- [3-fluoro-4- (3-methoxy-1-azetidinyl) phenyl] -2- oxo-5-oxazolidinyl] methyl] acetamide 2. (S) -N - [[3- [3-fluoro-4- (3-hydroxy-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl ] -acetamide 3. (S) -N - [[3- [3-fluoro-4- [3- [N- (2-fluoroethyl) -N-methylamino] -1-azetidinyl] phenyl] -2- 5-oxazolidinyl] methyl] acetamide 4. (S) -N - [[3- [3-fluoro-4- (3-oxo-1-azetldinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 5. (S) -N - [[3- [3-fluoro-4- [3- (methoxyimino) -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 6. (S) -N - [[3- [3-fluoro-4- (3-methoxy-3-methyl-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 16 ΕΡ Ο 788 498 / ΡΤ 7. ( S) -N - [[3- [3-fluoro-4- (3-hydroxy-3-methyl-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 8. (S) -N- [(3- [3-fluoro-4- (2-oxo-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 9. (S) -N - [[3- [3- fluoro-4- (3-hydroxy-2-oxo-1-azetidinyl) phenyl] -2-oxo-5-oxazolidine (3-fluoro-4- (3-methoxy-2-oxo-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 11. N - [[3- [3-fluoro-4- (3-methyl-2-oxo-1-azetidinyl) phenyl] -2-oxo- (5S) -oxazolidinyl) methyl] acetamide 12. (S) -N - [[3- [3-fluoro-4- (3,3-dimethyl-2-oxo-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (S) -N - [[3- [3-fluoro-4- [3- (hydroxyimino) -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 14. N - [[3- - [3-fluoro-4 - [(2R) -methyl-3-oxo-1-azetidinyl] phenyl] -2-oxo- (5S) -oxazolidinyl] methyl] acetamide 15. N - [[3- [3- fluoro-4 - [(2S) -methyl-3-oxo-1-azetidinyl] phenyl] -2-oxo- (5S) -oxazolidinyl] methyl] acetamide 16. N - [[3- [3-fluoro- [3- (3-Methoxyimino) (2R) -methyl-1-azetidinyl] phenyl] -2-oxo- (5S) -oxazolidinyl) methyl] acetamide 17. N - [[3- [3-fluoro- - (2S) -methyl-1-azetidinyl] phenyl] -2-oxo- (5S) -oxazolidinyl] methyl] acetamide 18. (S) -N - [[3- [3-fluoro-4- [3- - (difluoromethylene) -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

19. (S) -N - [[3- [3-fluoro-4- [3- (methoxymethylene) -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] acetamide 20. (S) -N - [[3- [3-fluoro-4- [3- (hydroxyacetyl) -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 21. (S) -N - [[3- [3-fluoro-4- [3- (methoxyamino) -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 22. N - [[3- - [3-fluoro-4- [2,4-dimethyl-3-oxo-1-azetidinyl] phenyl] -2-oxo- (5S) -oxazolidinyl] methyl] acetamide 23. N - [[3- [3-Fluoro -4- [2,4-dimethyl-3- (methoxyimino) -1-azetidinyl] phenyl] -2-oxo- (5S) -oxazolidinyl] methyl] acetamide 24. N - [[3- [3-fluoro-4- [ (S) -N - [[3- [3-fluoro-4 - [(3 S) -1- (3-methoxy- (S) -N - [[3- [3-fluoro-4 - [(3 R) -1- (4-methoxyphenyl) -2-oxo-5-oxazolidinyl] (S) -N - [[3- [3-fluoro-4- (3S) -hydroxy- (2S) -methyl-1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] 2R) -methyl-1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 28. (S) -N - [[3- [3- fluoro-4 - [(3R) -hydroxy- (2S) -methyl-1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 29. (S) -N - [[3- [3-fluoro- fluoro-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 30. (S) -N - [[3- [3-fluoro-4- [3-fluoro- (2R) - methyl-1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 18 (E) -N - [[3- [3-fluoro-4- [3-fluoro- (2S) (S) -N - [[3- [3-fluoro-4- [3 - [(hydroxyacetyl) amino] -2-oxo-4- -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 33. (S) -N - [[3- [3-fluoro-4- [3 - [(methanesulfonyl) amino] -1- azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 34. (S) -N - [[3- [3-fluoro-4- [3 - [(formyl) amino] -1-azetidinyl] phenyl ] - [[3- [3-fluoro-4- [3 - [(acetyl) amino] -1-azetidinyl] phenyl] (S) -N - [[3- [3-fluoro-4- [3 - [(methoxycarbonyl) amino] -1-azetidinyl] phenyl] -2- oxo-5-oxazolidinyl] methyl] acetamide 37. (S) -N - [[3- [3-fluoro-4- [3 - [(benzyl oxycarbonyl) amino] -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

The present invention discloses novel substituted pyrrolidinylphenyloxazolidinones according to Structural Formulas iv and v, above. The compounds are useful antimicrobial agents effective against various human and veterinary pathogens, particularly aerobic Gram-positive bacteria including antibiotic-resistant staphylococci and streptococci as well as anaerobic organisms such as bacteroid and clostridium species, and acid-resistant organisms such as Mycobacterium tuberculosis and other species of mycobacterium.

More preferred compounds in this series would be prepared as optically pure enantiomers having the (S) -configuration according to the Cahn-Ingold-Prelog notation at C5 of the oxazolidinone ring. The optically pure material could be prepared by one of several asymmetric syntheses or by resolution of a racemic modification by selective crystallization of a salt, for example, by the racemic modification of the intermediate amine 11 (as described in Scheme XII) with an appropriate optically active acid such as dibenzoyl tartrate or 10-camphorsulfonic acid, followed by treatment with base to provide the optically active amine. Although the (S) enantiomer of this series of compounds is preferred since it is pharmacologically active as an antibacterial agent, racemic modification is also useful in the same manner as the pure (S) enantiomer, the difference being that twice as much racemic material to cause the same antibacterial effect. Furthermore, it will be apparent to one skilled in the art that when a chiral center is present in the pyrrolidine moiety of the compounds of structural Formula IV and v diastereoisomers are possible. These diastereomers, in racemic or configuratively enriched forms, are also within the scope of the compounds of Formulas iv and v of this invention. The preferred preparation method for the pyrrolidinylphenyloxazolidinones of Formula IV and v in enantiomerically pure form is shown in Schemes XI-XIX. Schemes XI-XIX contain generic structural representations for the preparation of the various compounds of the invention centered around the cyclic structure of the nucleus where Q is iv or v.

As shown in Scheme XI, derivatives of structure 1, either commercially available or prepared by modification of literature methods, (US 4,753,953) may be protected with a diol, such as ethylene glycol, under acid catalysis conditions with azeotropic removal of water to form acetal 2. The N-benzyl group of 2 is then removed by hydrogenolysis in the presence of a noble metal catalyst such as palladium on carbon or palladium on carbon hydroxide in a suitable solvent to give the pyrrolidine derivative 3 The pyrrolidine derivative 3 may be treated with a nitrobenzene derivative 4 (Y = halogen or trifluoromethanesulfonate) in a combination of suitable base and solvent, for example dibasic potassium phosphate in DMSO and at a suitable temperature, typically ambient at 90 ° C, to afford the 5-adduct. The nitro group of 5 is then reduced by catalytic hydrogenation in the presence of catalysts such as palladium on carbon or Raney W-2 nickel in a suitable solvent, such as ethyl acetate or tetrahydrofuran (THF) to give the aniline derivative 6. When THF is used as solvent for this reduction, it is not necessary to remove the catalyst by filtration or to isolate the aniline derivative 6 but merely purging the reaction vessel with an inert gas such as saturated aqueous sodium bicarbonate solution with nitrogen and treating the resulting cooled mixture with benzyl or methyl chloroformate to give the corresponding benzyl derivatives (R 14 = CH 2 Ph) or methyl carbamate (R 14 = CH 3). Any of the carbamate derivatives 7 may be deprotonated with a lithium base such as n-butyl-lithium, lithium diisopropylamide (LDA), or bis (trimethylsilyl) amide (LHMDS) in a suitable solvent such as THF, N, N-dimethylformamide (DMF), or mixtures thereof, at a suitable temperature such as -78 ° C to -40 ° C to give a lithiated intermediate which is directly treated with (R) (-) - glycidyl butyrate. Heating this reaction mixture to room temperature then affords the (hydroxymethyl) oxazolidinones 8 in enantiomerically highly enriched form.

As shown in Scheme XII, compound 8 can be converted to the corresponding mesylate (R 15 = CH 3) or tosylate (R 15 = p-CH 3 C e H 4) by treatment with methanesulfonyl chloride in the presence of triethylamine or pyridine or p-toluenesulfonyl chloride in the presence of pyridine. The resulting sulfonate derivative 9 may then be treated with alkali metal azide such as sodium or potassium azide in a dipolar aprotic solvent such as DMF or N-methylpyrrolidinone (NMP) with an optional catalyst such as 18-crown-6 at a temperature in the range of 50-90 ° C to afford azide 10. Azide 10 may be reduced to the corresponding amine 11 by hydrogenation in the presence of a palladium, platinum or nickel catalyst in a suitable solvent such as ethyl acetate, THF, or methanol . Alternatively, azide 10 may be reduced by treatment with triphenylphosphine or other trivalent phosphorus compounds in a solvent such as THF, followed by addition of water. The amine 11 may also be prepared by treatment of sulfonate 9 with potassium phthalimidate in DMF at 40-90øC or in refluxing acetonitrile to afford the phthalimide 12 which is then deprotected by treatment with, for example, aqueous methylamine in refluxing ethanol affording 11. A more direct route to amine 11 is the treatment of the sulfonate 9 with aqueous ammonia solution in a solvent system isopropyl alcohol-THF in a sealed tube heated to 75-105 ° C in an oil bath. The amine 11 is then acylated by reactions well known to those skilled in the art to give (acylaminomethyl) oxazolidinones of structure 13. For example, the amine 11 may be treated with an acid chloride or anhydride in the presence of a base such as pyridine or triethylamine at temperatures ranging from -40-40 ° C to provide the acyl derivative 13 (R5 = optionally substituted alkyl). It is noticeable that; under similar reaction conditions; other acyl derivatives, such as carbamates, can easily be prepared. Finally, the treatment of 13 with acid 87 111 ΕΡ Ο 788 498 / ΡΤ 21

such as p-toluenesulfonic acid in aqueous acetone, will hydrolyze the acetal functionality to provide the corresponding carbonyl derivative 14 which represents an example of substituted pyrrolidinone antibacterial agents of Formula iv. It is apparent to those skilled in the art that other embodiments of a compound of Formula IV may be prepared from 14. Reaction of 14 with Lawesson's reagent or other alternative reagents such as hydrogen sulfide would provide the thioketone derivative 15 (R6 = S ). Oximes (Re = NHOH or NHOCH 3) may be prepared from 14 by treatment with hydroxylamine hydrochloride or methoxyamine hydrochloride in the presence of a base such as pyridine or sodium acetate in a solvent such as methanol. The hydrazone derivatives (R6 = NNHR12) may be prepared by treating 14 with hydrazine derivatives. Similarly, imines (R 6 = NR 12) may be prepared by treatment of 14 with a primary amine. Olefinic derivatives (R 6 = CR 11 R 12) may be prepared by treating 14 with various olefinating reagents such as phosphorus ylids (Wittig reagents), phosphonate esters (Horner-Emmons Reagents) or other reagents known to those skilled in the art. It can readily be seen that the reduction of the olefinic bond by catalytic hydrogenation or other methods will provide examples of Structural Formula v.

Schemes XIII-XV outline the preparation of examples of Structural Formula v where R 1 = OR 7, R 3 = H and n and n = 0. As shown in Scheme XIII, the intermediate 1 depicted in Scheme XI is reduced to alcohol 16 by treatment with any of various standard hydride reducing agents such as sodium borohydride, lithium aluminum hydride or the like. The benzyl protecting group of 16 can then be subsequently removed by hydrogenolysis using a catalyst such as palladium on carbon hydroxide, or 10% palladium on carbon to give the amino alcohol 17. It should be noted here that some examples of 17 may be commercially available , but the possibility of de novo synthesis of 17 has to be considered in order to include more complex examples of high antibacterial interest. The amino alcohol 17 may then be allowed to react with a nitrobenzene derivative such as 4 (Y = halogen or trifluoromethanesulfonate). in the presence of a suitable base such as dibasic potassium phosphate in a suitable solvent such as dimethylsulfoxide at temperatures in the range of 40-90 ° C to afford 18. It will be apparent to those skilled in the art that subsequent transformations of 18 will necessitate that the hydroxyl group protected. This can be achieved by

(R = Si (CH 3) 2 t -Bu) by treatment of 18 with tert-butyldimethylchlorosilane in the presence of a base such as imidazole or diisopropylethylamine, optionally tert-butyldimethylsilyl ether 19 (R = Si (CH 3) 2 t -Bu) in the presence of 4-dimethylaminopyridine as the catalyst, in a suitable solvent such as DMF, THF or dichloromethane. The nitro group of 19 may be reduced by hydrogenation in the presence of a catalyst such as 10% palladium on carbon or Raney W-2 nickel in a solvent such as THF or ethyl acetate to give the aniline derivative 20. The aniline derivative 20 is not is routinely isolated but is directly treated with saturated sodium bicarbonate and an alkyl chloroformate derivative such as benzyl chloroformate or methyl chloroformate to give the corresponding benzyl derivative (R 14 = CH 2 Ph) or methyl (R 14 = CH 3) carbamate 21. The derivative carbamate 21 may then be deprotonated by a base such as n-butyllithium or lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide (LHMDS) in a solvent such as THF or DMF or mixtures thereof, at a temperature in the range from -78 ° C to -40 ° C to give a lithiated derivative which is treated with commercially available (R) - (-) - glycidyl butyrate. The resulting mixture is then warmed to room temperature to give (hydroxymethyl) oxazolidinones 22. It is apparent to those skilled in the art that the oxazolidinone intermediate 22 can be used in various manners to prepare various embodiments of compounds of Formula IV. As shown in Scheme XIV, the oxazolidinone 22 can be converted to the (acylaminomethyl) oxazolidinone 23 by a sequence of reactions identical to that used to convert compound 8 to compound 13 in Scheme XII. The protecting group of 23 (R = Si (CH 3) 2t-Bu) may be removed by standard methods known to those skilled in the art, such as treatment with tetrabutylammonium fluoride in THF to afford alcohol 24, which is an example of a compound of Structural Formula v. Compound 24 may be converted into various derivatives 23 (R = R 7 = alkoxycarbonyl, carboxamide, optionally substituted acyl, etc.) by treatment with various carbonyl derivatives, such as anhydrides, acyl chlorides, alkyl and aryl chloroformates, isocyanates, and using appropriate bases and catalysts in suitable solvents known to a person skilled in the art. Thus, compounds 23 and 24 represent examples of oxazolidinone antibacterial agents of Structural Formula v.

Another use of the oxazolidinone intermediate 22 is illustrated in Scheme XV. As shown, 22 (R = Si (CH 3) 2t-Bu) may be protected, for example, by treatment with tert-butyldiphenylchlorosilane and a suitable base such as diisopropylethylamine and a catalyst such as 4-dimethylaminopyridine in a suitable solvent such as dichloromethane , THF or the like to give the bis-protected derivative 25 (R = Si (CH3) 2tBu, R1 = SiPh2t-Bu). The bis-protected derivative 25 is selectively deprotected to remove the tert-butyldimethylsilyl ether protecting group by treatment with acetic acid using a co-solvent of water and THF in a variety of proportions at temperatures ranging from 50-100øC to provide the alcohol 26 Alcohol 26 may be alkylated at the unprotected hydroxyl group by treatment with a suitable base, such as sodium hydride, in a dipolar aprotic solvent such as THF, DMF or the like, in the presence of an alkyl halide such as methyl iodide or substituted derivatives thereof to give silyl ether 25 (R = R7 = straight or branched chain alkyl, R1 = SiPh2 t-Bu). The silicon protecting group of 25 can then be removed by treatment with tetrabutylammonium fluoride in a solvent such as THF to afford the alcohol 27 (R = straight or branched chain alkyl). The alcohol 27 may then be converted to the (acylaminomethyl) oxazolidinone derivative 28 (R7 = straight or branched chain alkyl) by a sequence of reactions identical to that used to convert 8 to 13 in Scheme XII. The (acylaminomethyl) oxazolidinone derivative 27 is an example of an oxazolidinone antibacterial agent of Structural Formula v.

Schemes XVI-XIX outline the preparation of examples of Structural Formula v where R1 is the amino-substituted portion. Scheme XVI delineates the case where R 1 = NHR and n = 0. As shown, aminopyrrolidine 29 is either commercially available or prepared by methods well known in the art optionally protected either as trifluoroacetamide derivative (R = COCF3) or as tert-butoxycarbonyl derivative (R = CO2 t-Bu) is hydrogenolyzed in the presence of a suitable catalyst such as palladium on carbon hydroxide in an appropriate solvent such as methanol to remove the benzyl protecting group to provide pyrrolidine 30. Pyrrolidine 30 may be reacted with a nitroaromatic compound such as dimethylsulfoxide (DMSO) or DMF to provide the displacement product 31. The nitro group of 31 is reduced by hydrogenation in the presence of 10 % palladium on carbon or Raney W-2 nickel in a suitable solvent such as THF or ethyl acetate to provide the aniline derivative 32. The aniline derivative 32 is not routinely isolated but is generally directly treated with saturated sodium bicarbonate solution and an alkyl chloroformate derivative such as benzyl chloroformate or methyl chloroformate to give the corresponding benzyl derivative (R 14 = CH 2 Ph) or (R 14 = CH 3) carbamate 33. In case of being protected by an acyl derivative, it is necessary to remove the protecting group by appropriate means well known to those skilled in the art to provide the amine derivative primary amine 34. Amine 34 is then treated with a dialkylurea derivative such as Ν, Ν-dimethylurea or N, N-dibenzylurea in the presence of formaldehyde under conditions first used by Knapp, et al. to provide the dimethyl derivative R = CH 3) or dibenzyl (R = CH 2 Ph) triazone 35. The triazone 35 may then be deprotonated with a base such as n-butyllithium, lithium diisopropylamide (LDA) or naked lithium bis (trimethylsilyl) amide solvent such as DMF or mixtures of DMF and THF at temperatures in the range of -78Â ° to -40Â ° C to give a lithiated derivative which is directly treated with commercially available (R) - (-) - glycidyl butyrate. The resulting mixture is then warmed to room temperature to provide (hydroxymethyl) oxazolidinone 36. Scheme XVII describes the conversion of the triazone derivative 36 into compounds of Formula v. As shown, the triazone derivative 36 can be converted to the (acylaminomethyl) oxazolidinone 37 by means identical to those used to convert compound 8 to 13 in Scheme XII. The triazone group of 37 may be removed by hydrolysis with aqueous hydrochloric acid or by treatment with saturated ammonium chloride solution to afford the amine 38. Compound 38 may be converted into various carbonyl derivatives 39 (R = alkoxy, alkylamino, etc.) by treatment with various carbonyl derivatives such as acyl chlorides, anhydrides, alkyl and aryl chloroformates, isocyanates and the like, using appropriate bases and catalysts in suitable solvents known to one of ordinary skill in the art. In addition, compound 38 can be converted into various alkyl derivatives (R = optionally substituted straight or branched alkyl) by treatment with an appropriate aldehyde or ketone in the presence of hydrogen gas and a catalyst such as 10% palladium on carbon or a reagent such as sodium cyanoborohydride in a protic solvent such as methanol. Alternatively, it could be treated with an optionally substituted alkyl halide in the presence of a base such as sodium carbonate in a suitable solvent such as THF or acetonitrile, optionally in the presence of water. Compounds 39 and 40 thus prepared are examples of compounds of Formula v where n = 0. Scheme XVIII describes the preparation of examples of compounds of Structural Formula v where R 3 = H, R 1 = NR 8 R 9 and n = 1. As shown, the derivative pyrrolidine 41, available by known methods, 13.3 optionally protected either 87 111 ΕΡ Ο 788 498 / ΡΤ 25

as the trifluoroacetamide derivative (R = COCF3) or as tert-butoxycarbonyl derivative (R = CO2 t-Bu) is debenzylated by hydrogenolysis in the presence of a catalyst such as palladium on carbon hydroxide or 10% palladium on carbon in a suitable solvent such as methanol to yield 42. The pyrrolidine 42 may be allowed to react with a nitrobenzene derivative such as 4 in the presence of a base, such as potassium dibasic phosphate in a solvent such as dimethylsulfoxide (DMSO) to provide the aromatic displacement product 43. The arylpyrrolidine 43 may be reduced by hydrogenation in the presence of a catalyst such as 10% palladium on carbon or Raney W-2 nickel in a solvent such as THF or ethyl acetate to afford the aniline derivative 44. The aniline derivative 44 is not routinely isolated but in general is directly treated with saturated sodium bicarbonate solution and an alkyl chloroformate such as benzyl or methyl chloroformate (R 14 = CH 2 Ph) or methyl (R 14 -CH 3) carbamate 45. In case of being protected as an acyl derivative, it is necessary to remove the protecting group by suitable means well known to those skilled in the art to provide the primary amine derivative 46. The amine 46 is then treated with a dialkylurea derivative, such as Ν, Ν'-dimethylurea or Ν, Ν'-dibenzylurea in the presence of formaldehyde under conditions first used by Knapp, et al. providing the dimethyl (R = CH 3) or dibenzyl derivative (R = CH 2 Ph) triazone 47. The triazone 47 may be deprotonated with a base such as n-butyllithium, lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide in a solvent such as DMF or mixtures of DMF and THF at temperatures ranging from -78 ° to -40 ° C to give a lithiated derivative which is directly treated with commercially available (R) - (-) - glycidyl butyrate. The resulting mixture is then warmed to room temperature to give (hydroxymethyl) oxazolidinone 48. Scheme XIX describes the conversion of the triazone derivative 48 to the compounds of Structural Formula v. As shown, the triazone derivative 48 can be converted to the (acylaminomethyl) oxazolidinone 49 by means identical to those used to convert compound 8 to 13 in Scheme XII. The triazole group of 49 may be removed by hydrolysis with aqueous hydrochloric acid solution or by treatment with hot saturated ammonium chloride solution to provide amine 50. Amine 50 may then be converted into various carbonyl derivatives 61 (R = alkoxy, , optionally substituted alkyl, etc.) by treatment with various carbonyl derivatives, such as acyl chlorides, anhydrides, alkyl and aryl chloroformates, isocyanates, and the like, using suitable bases and catalysts in suitable solvents known to a person skilled in the art. In addition, the amine 50 may be converted into various alkyl derivatives 52 (R = optionally substituted straight or branched chain alkyl) by treatment of 50 with an appropriate aldehyde or ketone in the presence of hydrogen gas and a catalyst such as 10% palladium on carbon or a reagent such as sodium cyanoborohydride in a practical solvent such as methanol. Alternatively, 50 could be treated with an optionally substituted alkyl halide in the presence of a base such as sodium carbonate in a suitable solvent such as THF or acetonitrile, optionally in the presence of water to provide 52. Compounds 51 and 52 thus prepared constitute examples of oxazolidinone antibacterial agents of Structural Formula v, where n = 1.

It will be apparent to those skilled in the art that the synthetic procedures described are merely representative in nature and that alternative synthetic processes are known, for example some of them are described in the references cited.

Examples of pyrrolidinyl-phenyloxazolidinones which may be prepared as part of this invention are the following: 1. (S) -N - [[3- [3-Fluoro-4- (3-oxopyrrolidinyl) phenyl] -2-oxo- oxazolidinyl] methyl] acetamide 2. (S) -N - [[3- [3-Fluoro-4- (3-oxo-4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 3. ( S) -N - [[3- [3-Fluoro-4- (2,4-dimethyl-3-oxopyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 4. (S) -N - [[ (S) -N - [[3- [3-Fluoro-4- (2,2-dimethyl-3-oxopyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] (S) -N - [[3- [3-Fluoro-4- (4,4-dimethyl-3-oxopyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] 2,4-dimethyl-3-oxopyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] -methyl] acetamide hydrochloride 78E 498 / ΡΤ 7. (S) -N - [[3- [3-Fluoro-4- (S) -N - [[3- [3-Fluoro-4- (O-methyl-3-isonitrosopyrrolidinyl) phenyl] -2- (3-isonitrosopyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 9. (S) -N - [[3- [3-Fluoro-4- (3-hydroxypyrrolidinyl) phenyl] -2-oxo-5-oxazolid ynyl] methyl] -acetamide 10. (S) -N - [[3- [3-Fluoro-4- (cis-3-hydroxy-4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl ] acetamide 11. (S) -N - [[3- [3-Fluoro-4- (trans-3-hydroxy-4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] ) -N - [[3- [3-Fluoro-4- (3-methoxypyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 13. (S) -N - [[3- [3- Fluoro-4- (cis-3,4-dihydroxypyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 14. (S) -N - [[3- [3-Fluoro- (S) -N - [(3- [3-Fluoro-4- (3- (trans-3,4-dihydroxypyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] oxo-5-oxazolidinyl] methyl] acetamide 16. (S) -N - [[3- [3-Fluoro-4- [3- (phenylmethoxyacetylamino) pyrrolidinyl] phenyl] -2- oxo-5-oxazolidinyl] methyl] acetamide 17. (S) -N - [[3- [3-Fluoro-4- (3- (methoxyacetylamino) pyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl) methyl] acetamide 18. (S) -N - [[3- [3-Fluoro-4- (3- (methoxycarbonylamino) pyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 28 ΕΡ Ο 788 498 / ΡΤ 19 (S) -N- [(3- [3-Fluoro-4- (3- (ethoxycarbonylamino) pyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 20. (S) -N - [[3- [3- Fluoro-4- (cis-3- (phenylmethoxyacetylamino) -4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 21 (S) -N - [[3- [3-Fluoro-4- (S) -N - [[3- [3-Fluoro-4- (cis-3- (hydroxyacetylamino) -4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] 23. (S) -N - [[3- [3-Fluoro-4- (cis-3- (methoxycarbonylamino) methyl] (S) -N - [[3- [3-Fluoro-4- (cis-3- (ethoxycarbonylamino) -4-methyl-pyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] (S) -N - [[3- [3-Fluoro-4- (trans-3- (phenylmethoxyacetylamino) -4-methylpyrrolidinyl) phenyl] phenyl] ] -2-oxo-5-oxazolidinyl] methyl] acetamide 26. (S) -N - [[3- [3-Fluoro-4- (trans-3- (hydroxyacetylamino) -4-methylpyrrolidinyl) phenyl] -2- oxo-5-oxazolidinyl] methyl] acetamide 27. (S) -N - [[3- [3-Fluoro-4- (trans -3- (methoxyacetylamino) -4-methyl pyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 28. (S) -N - [[3- [3-Fluoro-4- (trans -3- (methoxycarbonylamino) -4-methylpyrrolidinyl) -2-oxo-5-oxazolidinyl] methyl] acetamide 29. (S) -N - [[3- [3-Fluoro-4- (trans-3- (ethoxycarbonylamino) -4-methylpyrrolidinyl) phenyl] -2-oxo (S) -N - [[3- [3-Fluoro-4- (3- (phenylmethoxyacetylamino) methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamid acetate 298 788 498 / ΡΤ 31. (S) -N - [[3- [3-Fluoro-4- (3-hydroxyacetylamino) methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (S) -N - [[3- [3-Fluoro-4- (3- (methoxyacetylamino) methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 33. (S) -N - [[ 3- (3-Fluoro-4- (3- (3-methoxycarbonylamino) methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 34. (S) -N - [[3- (S) -N - [[3- [3-Fluoro-4- (cis-3- (phenylmethoxyacetylamino) methyl] -3-methyl- -4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] meth yl] acetamide 36. (S) -N - [[3- [3-Fluoro-4- (cis-3- (hydroxyacetylamino) methyl-4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 37. (S) -N - [[3- [3-Fluoro-4- (cis-3- (methoxyacetylamino) methyl-4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (S) -N - [[3- [3-Fluoro-4- (cis-3- (methoxycarbonylamino) methyl-4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 39. (S) ) N - [[3- [3-Fluoro-4- (cis-3- (ethoxycarbonylamino) methyl-4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 40. (S) - N - [[3- [3-Fluoro-4- (trans-3- (phenylmethoxyacetylamino) methyl-4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 41. (S) N- [S] -N- [3-Fluoro-4- (trans-3- (hydroxyacetylamino) methyl-4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 42. (S) [3- [3-Fluoro-4- (trans-3- (methoxyacetylamino) methyl-4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 30 87 111 ΕΡ Ο 788 498 / ΡΤ 43. S) -N - [[3- [3-Fluoro-4- (trans-3- (methoxycarbonylamino) methyl-4-methylpyrrolidinyl yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 44. (S) -N - [[3- [3-Fluoro-4- (trans-3- (ethoxycarbonylamino) methyl-4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide 4B (S) -N - [[3- [3-Fluoro-4- [trans -3- (phenylmethoxy) acetylamino-4-hydroxypyrrolidinyl] phenyl] - Oxo-5-oxazolidinyl] methyl] acetamide 46. (S) -N - [[3- [3-Fluoro-4- (trans -3- (methoxyacetylamino) -4-hydroxypyrrolidinyl) phenyl] -2-oxo -5-oxazolidinyl] methyl] acetamide 47. (S) -N - [[3- [3-Fluoro-4- (trans -3- (methoxycarbonylamino) -4-hydroxypyrrolidinyl) phenyl] -2-oxo -5-oxazolidinyl] methyl] acetamide 48. (S) -N - [[3- [3-Fluoro-4- (trans -3- (ethoxycarbonylamino) -4-hydroxypyrrolidinyl) phenyl] -2- oxazolidinyl] methyl] acetamide

Antibacterial Activity

The oxazolidinone antibacterial agents of this invention have useful activity against various organisms. The in vitro activity of the compounds of this invention can be evaluated by standard test procedures such as determination of the minimal inhibitory concentration (MIC) by dilution with agar as described in " Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically " (MFT) published Jan. 1983 by the National Committee for Clinical Laboratory Standards, 771 East Lancaster Avenue, Villanova, Pennsylvania 19084, USA. The activity of the selected compounds of this invention against Staphylococcus aureus and Streptococcus pneumoniae is shown in Table 1. 31 ΕΡ Ο 788 498 / ΡΤ

Table 1

Minimum Inhibitory Concentration (pg / mL)

Example No. S. aureus UC® 9213 S. pneumoniae UC®9912 1 4 2 2 4 2 3 16 8 4 1 0.5 5 4 1 6 8 4 7 8 2 8 32 8 9 8 2 10 2 1 11 4 2 12 8 2 13 16 2 14 4 1 15 16 2 16 8 1 vancomycin 1 0.5

Azetidinyl-Phenyloxazolidinones EXAMPLE 1: (S) -N- [3- [3-fluoro-4- (3-methoxy-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

Step 1: 1- (diphenylmethyl) -3-methoxyazetidine

A slurry of sodium hydride (0.440 g of a 60% dispersion in oil, 11.0 mmol) in dry tetrahydrofuran (125 mL) under nitrogen was cooled with an ice bath to 0øC and treated with 1- (diphenylmethyl) -3-azetidinol (2.393 g, 10.0 mmol) over 5 min. After stirring for 30 min at 0 ° C, iodomethane (1.490 g, 0.654 mL, 10.5 mmol) was added. When the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into phosphate buffer pH 7 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was chromatographed on silica gel.

(300 mL) packed with dichloromethane, eluting with a gradient of 1-10% ethyl acetate / dichloromethane. Concentration of the appropriate fractions afforded 2.081 g (82%) of the title compound as a light yellow syrup with MS (EI) 253 (M +).

Step 2: 3-fluoro-4- (3-methoxy-1-azetidinyl) nitrobenzene

A solution of 1- (diphenylmethyl) -3-methoxyazetidine (2.000 g, 7.91 mmol) in 25% tetrahydrofuran / ethanol (100 mL) was treated with 5 N HCl (5.0 mL) and palladium hydroxide on carbon (Pearlman's catalyst, 0.500 g). The mixture was shaken in a Parr apparatus under 45 psi H2. After 16 h some starting material still remained, by TLC analysis (silica gel, 6% acetonitrile / chloroform). An additional 0.500 g of Pearlman's catalyst was added and the hydrogenolysis was continued for a further 16 h at which time the reaction appeared to be complete. The reaction mixture was filtered through Celite® and the filtrate concentrated under reduced pressure to an amber oil. This material was dissolved in dimethylsulfoxide (30 mL) and treated with dipotassium hydrogen phosphate (6.88 g, 39.6 mmol) and 3,4-difluoronitrobenzene (1.05 mL, 9.49 mmol). The reaction mixture was stirred at room temperature for 16 h, at which time TLC (silica gel, 6% acetonitrile / chloroform) showed the reaction complete. The reaction mixture was diluted with water (150 mL) and extracted with chloroform (3 x 40 mL). The combined organic extracts were washed with water (3 x 25 mL) and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product. Purification was achieved by silica gel chromatography (100 g), eluting with a gradient of 0-1% acetonitrile / chloroform. Concentration of the appropriate fractions then afforded 1.50 g (84%) of the title compound as a bright yellow solid with mp 57.5-58øC and MS (EI) 226 (M +).

Step 3: N- (carbobenzyloxy) - (3-fluoro-4- (3-methoxy-1-azetidinyl) aniline

A solution of 3-fluoro-4- (3-methoxy-1-azetidinyl) nitrobenzene (1.50 g, 6.64 mmol) in 1: 1 methanol / tetrahydrofuran (35 mL) was treated with 10% carbon dioxide and then ammonium formate (1.26 g, 19.9 mmol) at room temperature. 33 ΕΡ Ο 788 498 / ΡΤ

After 20 min the color of the reaction mixture changed from yellow to colorless. The reaction mixture was filtered through Celite® and the filtrate concentrated under reduced pressure. The recovered oil was immediately dissolved in 3: 1 acetone / water (25 mL) and treated with potassium carbonate (2.75 g, 19.9 mmol) and benzyl chloroformate (1.31 mL, 8.30 mmol). After 30 min, TLC (6% acetonitrile / chloroform) analysis revealed that the reaction was complete. The reaction mixture was extracted with chloroform (3 x 20 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a purple oil. This material was chromatographed on silica gel (100 g), eluting with a gradient of 1-3% acetonitrile / chloroform, to give, after concentration of the appropriate fractions, 1.24 g (56%) of the title compound as a white solid. a white-off solid with mp 95-96.5 ° C and MS (EI) 330 (M +).

Step 4: (R) [3- (3-fluoro-4- (3-methoxy-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methanol

A solution of N- (carbobenzyloxy) -3-fluoro-4- (3-methoxy-1-azetidinyl) aniline (0.865 g, 2.62 mmol) in dry tetrahydrofuran (10 mL) was cooled to -78 ° C under nitrogen atmosphere and treated with n-butyllithium (1.65 mL of a 1.6 M solution in hexanes, 2.65 mmol). After stirring at -78 ° C for 15 min, the reaction mixture was treated with (R) -glycidyl butyrate (0.374 mL, 2.65 mmol). The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature. After 1 h the reaction was considered complete by TLC analysis. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (0.5 mL) and concentrated under reduced pressure to give a yellow solid. Chromatography on silica gel (10 g), eluting with a gradient of 1-2% methanol / chloroform gave, after concentration of the appropriate fractions, 0.530 g (68%) of the title compound as a white solid, mp 131-132 ° C and MS (EI) 296 (M +).

Step 5: (R) -3- [3-fluoro-4- (3-methoxy-1-azetidinylphenyl) -2-oxo-5-oxazolidinyl] methyl] methanesulphonate

A solution of (R) - [3- [3-fluoro-4- (3-methoxy-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methanol (0.492 g, 1.66 mmol) in dry dichloromethane mL) under nitrogen was cooled with an ice bath to 0 ° C and treated with triethylamine (0.254 mL, 1.83 mmol) followed by methanesulfonyl chloride (η 788 498 / ΡΤ (0.141 mL, 83 mmol). After 1 h at 0 ° C, TLC (10% methanol / chloroform) analysis revealed that the reaction was complete. The reaction mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a white solid. Chromatography on silica gel (100 g), eluting with a gradient of 1-3% methanol / chloroform gave, after concentration of the appropriate fractions, 0.601 g (97%) of the title compound as a white solid with mp 122 DEG. , 5-123.5 ° C and MS (EI) 374 (M +).

Step 6: (R) - [[3- [3-fluoro-4- (3-methoxy-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinylmethyl] 3-methoxy-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] methanesulfonate (0.508 g, 1.36 mmol) was combined with sodium azide (0.106 g, 1.63 mmol) in Ν, The reaction mixture was heated at 65 DEG C. under nitrogen atmosphere After 2 hours, a small amount of the starting mesylate still remained, by TLC analysis (5% methanol / chloroform). The residue was chromatographed on silica gel (25 g), and the residue was chromatographed over silica gel (25 g) ), eluting with a gradient of 1-3% methanol / chloroform The appropriate fractions were combined and concentrated in vacuo to provide 0.446 g (98%) of the title compound as an off-white solid. analytical sample by recrystallization of this material from 3: 1 ethyl acetate / hexane to give a white solid with mp 111-112.5 ° C and MS (EI) 321 (M +).

Step 7: (S) -N- [3- [3-fluoro-4- (3-methoxy-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] iminacetamide

A solution of (R) - [[3- [3-fluoro-4- (3-methoxy-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] azide (0.393 g, 1.22 mmol) in methanol / dichloromethane 5: 1 (20 mL) was treated with 10% palladium on carbon (0.030 g) under a stream of nitrogen. The atmosphere was then replaced with hydrogen (flask). After stirring 3 hours under hydrogen, the reduction was considered complete by TLC (5% methanol / chloroform) analysis. The reaction mixture was filtered through Celite® and concentrated under reduced pressure. The crude 5- (aminomethyl) oxazolidinone was dissolved in dichloromethane (15 mL) and treated with pyridine (0.118 mL, 1.46 mmol) and anhydride

(0.138 mL, 1.46 mmol) under a nitrogen atmosphere at room temperature. After 2 h, the reaction was considered complete by TLC. The reaction mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography on silica gel (50 g), eluting with a gradient of 1-3% methanol / chloroform, gave, after concentration of the appropriate fractions, 0.281 g (68%) of the title antibacterial agent as a white solid. An analytical sample, prepared by recrystallization from 2: 1 ethyl acetate / hexane, was a white solid with m.p. 160-161.5 ° C and MS (EI) 337 (M +). EXAMPLE 2 (S) -N- [3- (3-fluoro-4- (3-hydroxy-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

Step 1: 3-fluoro-4- (3-hydroxy-1-azetidinyl) nitrobenzene

1- (Diphenylmethyl) -3-azetidinol hydrochloride (2.000 g, 7.29 mmol) was dissolved in methanol (75 mL) and treated with 6N HCl (1.20 mL, 7.29 mmol). Palladium hydroxide on carbon (0.200 g) was then added under a stream of nitrogen. The reaction mixture was then shaken in a Parr apparatus under 40 psi H2. After 16 h, TLC (5% methanol / chloroform) analysis revealed that the starting material was consumed. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to an amber oil. This material was dissolved in dimethylsulfoxide (29 mL) and the atmosphere was replaced with nitrogen. Dipotassium hydrogen phosphate (5.07 g, 29.2 mmol) was added followed by 3,4-difluoronitrobenzene (0.966 mL, 8.75 mmol). The mixture was stirred at room temperature under nitrogen. After 3 h, TLC (5% methanol / chloroform) analysis revealed that the reaction was complete. The reaction mixture was diluted with water (250 mL) and extracted with chloroform (4 x 50 mL). The combined organic extracts were washed with water (2 x 50 mL) and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow solid. Chromatography on silica gel (100 g), eluting with a gradient of 3-7% acetonitrile / chloroform gave, after concentration of the appropriate fractions, 1.00 g (65%) of the title compound as a colorless solid, of orange with mp 130.5-132 ° C and MS (EI) 212 (M +).

Step 2: 4- [3-tert-Butyldimethylsilyloxy] -1-azetidinyl] -3-fluoronitrobenzene

A solution of 3-fluoro-4- (3-hydroxy-1-azetidinyl) nitrobenzene (5.51 g, 26.0 mmol) in N, N-dimethylformamide (104 mL) under nitrogen was cooled to 0 ° C with

(1.86 g, 27.3 mmol) followed by tert-butyldimethylsilyl chloride (4.12 g, 27.3 mmol). The reaction mixture was stirred at 0 ° C for 30 min and then at room temperature overnight. TLC analysis (5% methanol / chloroform) at this time revealed that a small amount of starting material remained. An additional amount of tert-butyldimethylsilyl chloride (0.392 g) was added. After stirring overnight, TLC analysis indicated that the reaction was complete. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (4 x 70 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid. Chromatography on silica gel (200 g), eluting with 5% and 10% ethyl acetate / hexane, afforded, after concentration of the appropriate fractions, 6.30 g (74%) of the title compound as a yellow solid mp 98.5-99.5 ° C and MS (EI) 326 (M +).

Step 3: 4- [3 - [(tert-Butyldimethylsilyl) oxy] -1-azetidinyl] -3-fluoronitrobenzene (1.00 g , 3.07 mmol) was combined with 10% palladium on carbon (0.100 g) in 3: 1 tetrahydrofuran / water (25 mL) under a nitrogen atmosphere. The atmosphere was replaced with hydrogen (balloon) by repeated evacuation and filling The reaction mixture was filtered through a pad of Celite® and the filtrate was immediately placed under an atmosphere of ethyl acetate / hexane to give the title compound as a yellow oil (15% ethyl acetate / hexane / ethyl acetate / hexane / ethyl acetate / hexane / ethyl acetate / hexane) hexane) indicated that the reaction was complete.The reaction mixture was concentrated under reduced pressure to give a white, off-white solid. silica gel (125 g), eluting with a gradient of 5-30% ethyl acetate / hexane, afforded, after concentration of the appropriate fractions, 0.565 g (43%) of the title compound as a white solid with mp 91-93 ° C and MS (EI) 430 (M +) 37 87 111 ΕΡ Ο 788 498 / ΡΤ

Step 4: (R) - [3- [4- [3- (tert-butyldimethylsilynoxy] -1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methanol

A solution of N- (carbobenzyloxy) -4- [3 - [(tert-butyldimethylsilyl) oxy] -1-azetidinyl) -3-fluoroaniline (6.30 g, 14.7 mmol) in dry tetrahydrofuran (100 mL ) under nitrogen was cooled to -78 ° C and treated with n-butyllithium (9.16 mL of a 1.6 M solution in hexanes, 14.7 mmol). When the addition was complete, the reaction mixture was stirred at -78 ° C for 15 min and then treated with (R) -glycidyl butyrate (2.21 mL, 14.7 mmol). After the addition was complete, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 1.5 h. At this time, saturated aqueous ammonium chloride (20 mL) was added. After 3 min, saturated aqueous sodium bicarbonate (10 mL) was added to the reaction mixture and the organic solvent was removed by rotary evaporation under reduced pressure. Dichloromethane (100 mL) was added and the mixture washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. Chromatography on silica gel (200 g) eluting with a gradient of 1-3% methanol / chloroform afforded, after concentration of the appropriate fractions, 4.39 g (75%) of the title compound as a white solid mp 189-186 ° C and MS (EI) 396 (IVT).

(R) - [3- [4- [3- (4-Fluoro-phenyl) -2-oxo-5-oxazolidinylmethyl] -methanesulfonate [(tert-butyldimethylsilyl) oxy] -1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methanol (5.38 g, 13.6 mmol) was dissolved in dry dichloromethane (70 mL), cooled at 0 ° C with an ice bath, and treated with triethylamine (2.08 mL, 14.9 mmol) and then with methanesulfonyl chloride (1.15 mL, 14.9 mmol). After 30 min at 0 ° C, the reaction was complete by TLC analysis (5% methanol / chloroform). The reaction mixture was washed with saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a white, off-white solid. An analytical sample, prepared by triturating the crude product with isopropanol and diethyl ether, followed by filtration and drying in vacuo, gave a white solid, m.p. 142-145Â ° C and MS (EI) 474 (M +). 38 87 111 ΕΡ Ο 788 498 / ΡΤ

(R) - [[3- [4- [3 - [((R) - [[3- (4-Fluorophenyl-2-oxazolidinyl] tert-Butyldimethylsilyl) oxy] -1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] methanesulfonate (9.42 mmol) was dissolved in dry N, N-dimethylformamide (50 mL) and treated with sodium azide (4.42 g, 68.0 mmol) at ambient temperature. The reaction mixture was heated at 65 ° C under nitrogen for 4 h. TLC analysis (5% methanol / chloroform) at this time revealed that The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3 x 25 mL) and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an amber solid. eluting with a gradient of 10-20% ethyl acetate / hexane, afforded, after concentration of the appropriate fractions, 2.21 g (56% for 3 steps) of the title azide as a white solid. white solid, mp 121-122.5 ° C and MS (EI) 421 (M +).

Step 7: (S) -N- [3- [4- [3- (tert-butyldimethylsilyloxy) -1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A solution of (R) - [[3- [4- [3 - [(tert-butyldimethylsilyl) oxy] -1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] 04 g, 4.85 mmol) in 1: 1 ethyl acetate / methanol (200 mL) was treated with 10% palladium on carbon (0.300 g) under a stream of nitrogen. The atmosphere was then replaced by H2 (flask) by repeated evacuation and filling. After 3 h, TLC (5% methanol / chloroform) analysis revealed that the reduction was complete. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give a white solid. The crude 5- (aminomethyl) oxazolidinone was dissolved in dichloromethane (100 mL), cooled to 0øC under a nitrogen atmosphere, and treated with pyridine (0.431 mL, 5.33 mmol) and acetic anhydride (0.503 mL, , 33 mmol). After 30 min at 0 ° C, the acetylation was complete by TLC (5% methanol / chloroform). The reaction mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product as a tan solid. Chromatography on silica gel (125 g) eluting with a gradient of 1-3% methanol / chloroform afforded, after concentration of the appropriate fractions, 1.77 g (84%) of the title compound as a white solid mp 183.5-184øC and MS (EI) 437 (M +).

87 111 ΕΡ Ο 788 498 / ΡΤ 39

Step 8: (S) -N- [3- (3-fluoro-4- (3-hydroxy-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A solution in acetonitrile (55 mL) of (S) -N - [[3- [4- [3 - [(tert-butyldimethylsilyl) oxy] -1-azetidinyl] -3-fluorophenyl] -2- oxazolidinyl] methyl] acetamide (1.23 g, 2.81 mmol) in a polypropylene bottle was treated with 38% aqueous hydrofluoric acid (15 mL) at room temperature. TLC analysis revealed that the deprotection was complete after 3 h. The reaction mixture was diluted with water (15 mL) and neutralized with solid sodium bicarbonate. Additional water (50 mL) was added and the mixture was extracted with chloroform. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title antibiotic oxazolidinone as a white solid, mp 174-177 ° C and MS (EI ) 323 (M +). EXAMPLE 3 (S) -N- [3- [3-fluoro-4- [3- (2-fluoroethyl) -N-methylamino] -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinylmethyl] acetamide

Step 1: 1- (Diphenylmethyl) -3- (2-fluoroethyl) -N-methylaminolazetidine 1- (Diphenylmethyl) -3- (methylamino) azetidine (5.00 g, 19.8 mmol) was combined with potassium (16.4 g, 119 mmol) and 2-fluoroethyl tosylate (6.50 g, 29.8 mmol) in 6% water / acetonitrile (200 mL). The mixture was heated at reflux temperature under a nitrogen atmosphere. After 3 h at reflux, TLC (5% methanol / chloroform) analysis revealed that a small amount of starting material remained. 1.8 g of additional 2-fluoroethyl tosylate was added and the reaction mixture was refluxed for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Chromatography on silica gel (200 g), eluting with a gradient of 1-5% acetonitrile / chloroform, afforded, after concentration of the appropriate fractions, 4.07 g (69%) of the title compound as an amber syrup with IR 1598.1452,1362.1029 cm -1.

Step 2: 3-fluoro-4- [3- (2-fluoroethyl) -N-methylamino] -1-azetidinylnitrobenzene

A bottle of Parr was charged with 1- (diphenylmethyl) -3- [N- (2-fluoroethyl) -N-methylamino] azetidine (3.88 g, 13.0 mmol) and 25% tetrahydrofuran / ethanol (130 mL) . Palladium on carbon hydroxide (1.9 g) was then added under a stream of 87 111 Ρ Ρ 788 498 / ΡΤ 40

nitrogen. The mixture was then shaken on a Parr apparatus under 45 psi H2. After 20 hours, TLC (5% methanol / chloroform) analysis revealed that the hydrogenolysis was complete. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to a colorless oil. This material was dissolved in dimethylsulfoxide (50 mL) and treated with dipotassium hydrogenphosphate (13.6 g, 78.0 mmol) followed by 3,4-difluoronitrobenzene (1.72 mL, 15.6 mmol). The reaction mixture was then stirred at room temperature and the progress of the reaction monitored by TLC analysis (5% methanol / chloroform). After 4 hours, the reaction mixture was added to H2O (500 mL) and extracted with dichloromethane (4 x 75 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow syrup. Chromatography on silica gel (200 g), eluting with a gradient 0-2.5% acetonitrile / dichloromethane, afforded, after concentration of the appropriate fractions, 2.87 g (81%) of the title compound as a solid yellow with mp 46.5-48 ° C and MS (FAB) 272 (M + H) +.

Step 3: N- (Carbobenzyloxy) -3-fluoro-4- [3- [N- (2-fluoroethyl) -N-methylamino] -1-azetidinyl] aniline

A solution of 3-fluoro-4- [3- [N- (2-fluoroethyl) -N-methylamino] -1-azetidinyl] nitrobenzene (2.66 g, 9.82 mmol) in tetrahydrofuran / water 2: 1 (50 mL) and acetic acid (2.0 mL) was treated with 10% palladium / carbon under a stream of nitrogen. The atmosphere was replaced with H2 (flask) by repeated evacuation and filling and the reaction mixture was stirred under H2 overnight. TLC analysis (6% acetonitrile / chloroform) at this time revealed that the reduction was complete. The reaction mixture was filtered on Celite®. Exposure to air was minimized since a purple color developed rapidly under these conditions. The filtrate was cooled with an ice bath to about 0 ° C and treated with potassium carbonate (6.8 g, 49 mmol) and benzylchloroformate (1.63 mL, 10.3 mmol). The reaction mixture was stirred at about 0 ° C for 1 h and then warmed to ambient temperature for 30 min. TLC analysis (6% acetonitrile / chloroform) at this time revealed that the reaction was complete. The reaction mixture was diluted with water (200 mL) and extracted with chloroform (3 x 75 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a dark amber syrup. Chromatography on silica gel (200 g) eluting with a gradient of 1-3% methanol / chloroform afforded, after concentration of the fractions

3.71 g (100%) of the title compound as an amber syrup. An analytical sample was prepared by additional chromatographic purification to give a light amber solid with mp 57-59Â ° C and MS (EI) 375 (IVT).

Step 4: (R) -N- [3- [3-fluoro-4- [3- (2-fluoroethyl) -N-methylamino] -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol

A solution of N- (carbobenzyloxy) -3-fluoro-4- [3- [N- (2-fluoroethyl) -N-methylamino] -1-azetidinyl] aniline (3.38 g, 9.01 mmol) in tetra (40 mL) under nitrogen was cooled to -78øC and treated with n-butyllithium (5.69 mL of a 1.6 M solution in hexane, 9.10 mmol). The reaction mixture was warmed to -40 ° C and then recooled to -78 ° C and treated with (R) -glycidyl butyrate (1.29 mL, 9.10 mmol). When the addition was complete, the reaction mixture was allowed to warm to room temperature. After 1 h, the reaction appeared to be completed by TLC analysis (5% methanol / chloroform). The reaction mixture was quenched with saturated aqueous ammonium chloride (1 mL), diluted with water (100 mL) and extracted with chloroform (3 x 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give an amber syrup. Chromatography on silica gel (200 g), eluting with a gradient of 1-4% methanol / chloroform, afforded, after concentration of the appropriate fractions, 1.69 g (55%) of the title compound as a solid white solid, mp 124-125Â ° C and MS (EI) 341 (M +).

Step 5: (R1- [3- [4- [3- [3- (2-Fluoroethyl) -N-methylamino] -1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methanesulfonate

A solution of (R) -N- [3- [3-fluoro-4- [3- [N- (2-fluoroethyl) -N-methylamino] -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl ] methanol (1.40 g, 4.11 mmol) in dry dichloromethane (16 mL) was treated with triethylamine (0.628 mL, 4.52 mmol) and then cooled to 0øC under a nitrogen atmosphere. Methanesulfonyl chloride (0.348 mL, 4.52 mmol) was then added and the mixture was stirred at 0 ° C. TLC analysis (5% methanol / chloroform) after 2 h showed still a small amount of starting material remained. An additional portion of methanesulfonyl chloride (0.100 mL, 1.30 mmol) was added and the reaction was continued for another 1 h at 0 ° C. The reaction mixture was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to give 1.88 g (100%) of the title compound as a light orange solid. 1 H NMR analysis indicated that this material was of high quality. An analytical sample was prepared by chromatographing 200 mg of the crude product on silica gel (10 g), eluting with a gradient of 1-4% methanol / chloroform, to provide, after concentration of the appropriate fractions, 99 mg of the title compound as a white solid. a white solid with mp 96.5-98øC and MS (EI) 419 (M +).

Step 6: (R) - [3- [4- (3-N- (2-Fluoroethyl) -N-methylamino] -1- (4-fluorothienyl] -3-fluorophenyl-2-oxo-5-oxazolidinecarboxamide

A solution of (R) - [[3- [4- [3- [N- (2-fluoroethyl) -N-methylamino] -1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl ] methanesulfonate (1.65 g, 3.94 mmol) in dry N, N-dimethylformamide (15 mL) was treated with solid sodium azide (0.768 g, 11.8 mmol). The reaction mixture was then heated to 65 ° C under a nitrogen atmosphere. After 3 h, TLC (5% methanol / chloroform) analysis revealed that a small amount of starting mesylate still remained. An additional portion of sodium azide (0.256 g, 3.94 mmol) was added and the reaction mixture was heated at 65 ° C for 1 h. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (100 g), eluting with a gradient of 1-4% methanol / chloroform, to afford, after concentration of the appropriate fractions, 1.24 g (86%) of the title compound as a white solid of a white-off solid with mp 60-63 ° C and MS (EI) 366 (M +).

Step 7: (S) -N- [3- (3-fluoro-4- {3- [N- (2-fluoroethyl) -N-methylamino] -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A solution of (R) - [[3- [4- [3- [N- (2-fluoroethyl) -N-methylamino] -1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl ] azide (1.14 g, 3.11 mol) in methanol (20 mL) was treated with 10% palladium / carbon (0.114 g) under a stream of nitrogen. The atmosphere was replaced with H2 (flask) by repeated evacuation and filling. After 2.5 h, TLC (5% methanol / chloroform) analysis revealed that the reduction was complete. The reaction mixture was filtered through Celite® and the filtrate concentrated under vacuum to give a white-off solid. This material was dissolved in dichloromethane (20 mL) and treated with pyridine (0.264 mL, 3.27 mmol) and acetic anhydride (0.309 mL, 3.27 mmol) under nitrogen. After 30 min, TLC analysis (5% methanol / chloroform) indicated that the acetylation was complete. The reaction mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give an amber oil. 1H NMR (DMSO-d6):? Chromatography on silica gel (125 g), eluting with a gradient of λ-4% methanol / chloroform, gave 0.892 g (75%) of the title oxazolidinone antibacterial agent after concentration of the appropriate fractions as a white solid mp 125.5-127 ° C and MS (EI) 382 (M +). EXAMPLE 4: (S) -N- [3- [3-fluoro-4- (3-oxo-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A solution of (S) -N - [[3- [3-fluoro-4- (3-hydroxy-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (EXAMPLE 2, 0.440 g, 1.36 mmol ) in 10% acetonitrile / dichloromethane (100 mL) was treated with 4 angstrom powdered molecular sieves (0.682 g), 4-methylmorpholine N-oxide (0.319 g, 2.72 mmol) and then tetra-n-butyl perruthenate (0.024 g, 0.068 mmol) at room temperature. After stirring 1.5 hours at room temperature, TLC (10% methanol / chloroform) analysis revealed that a small amount of starting alcohol still remained. Addition of additional 4-methylmorpholine N-oxide did not consume the starting material. The reaction mixture was concentrated under reduced pressure to a dark purple solid which was then chromatographed on silica gel (20 g) eluting with a gradient of 1-3.5% methanol / chloroform to afford, after concentration of the appropriate fractions, 0.204 g (47%) of the title antibacterial oxazolidinone as a white solid with mp 192-193øC and MS (EI) 321 (M +). EXAMPLE 5 (S) -N- [3- [3-fluoro-4- [3- (methoxyimino) -1-azetidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A solution of (S) -N - [[3- [3-fluoro-4- (3-oxo-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (EXAMPLE 4, 0.200 g, 0.623 mmol) in 5% methanol / dichloromethane (10 mL) was treated with pyridine (0.201 mL, 2.49 mmol) and then methoxylamine hydrochloride (0.052 g, 0.623 mmol) at room temperature. After 1.5 hours, TLC (10% methanol / chloroform) analysis revealed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a white solid. Chromatography on silica gel (10 g) eluting with a gradient of 1-3% methanol / chloroform afforded, after concentration of the appropriate fractions, 0.204 g (94%) of the antibacterial agent

The title compound was obtained as a white-solid solid. The title compound was obtained as a white solid. 1H-NMR (DMSO-d6):? A further synthetic passage provided material with mp 189-192 ° C and MS (EI) 350 (M +). EXAMPLE 6: (S) -N- [3- (3-Fluoro-4- (3-methoxy-3-methyl-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

Step 1: 1- (diphenylmethyl) -3-methoxy-3-methylazetidine

A slurry of 1- (diphenylmethyl) -3-methyl-3-azetidinol hydrochloride (5.00 g, 17.2 mmol) in dry tetrahydrofuran (200 mL) was cooled with an ice bath to 0øC and treated with sodium hydride (2.10 g of a 60% dispersion in oil, 51.8 mmol) under nitrogen. The cooling bath was removed and the mixture was heated at reflux temperature for 15 min. After cooling to room temperature, iodomethane (7.40 g, 3.22 mL, 51.8 mmol) was added. When the addition was complete, the reaction mixture was heated at reflux temperature for 15 hours. TLC analysis (9: 1 hexane / ethyl acetate) showed methylation to be complete. The reaction mixture was quenched with saturated aqueous ammonium chloride. The mixture was transferred to a separatory funnel with ethyl acetate and water and then extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was chromatographed on silica gel, eluting with 9: 1 ethyl acetate / hexane. Concentration of the appropriate fractions afforded 2.30 g (50%) of the title compound as a colorless oil with MS (EI) 267 (M +).

Step 2: 3-fluoro-4- (3-methoxy-3-methyl-1-azetidininnitrobenzene

A solution of 1- (diphenylmethyl) -3-methoxy-3-methylazetidine (2.20 g, 8.2 mmol) in 25% tetrahydrofuran / ethanol was treated with glacial acetic acid (1.60 g, 1.50 mL, 24.7 mmol) and then with palladium hydroxide on carbon (0.220 g) under a stream of nitrogen. The reaction mixture was shaken on a Parr apparatus under 35 psi H2. At this point, TLC (hexane / ethyl acetate 9: 1) showed the reaction complete. The mixture was filtered through Celite® (washing with ethyl acetate) and the filtrate concentrated under vacuum to give an oil. This material was dissolved in dimethylsulfoxide (15 mL) and the solution treated with dipotassium hydrogen phosphate (8.60 g, 49.2 mmol) and 3,4-difluoronitrobenzene (1.30 g, 0.886 mL, 8.0 mmol) at room temperature. The yellow reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and dried in vacuo to give a yellow solid. Chromatography on silica gel, eluting with 8: 1 hexane / ethyl acetate, afforded, after concentration of the appropriate fractions, 1.80 g (90%) of the title compound as a yellow solid, mp 110-111ø C and MS (EI) 240 (M +).

Step 3: N- (carbobenzyloxy) -3-fluoro-4- (3-methoxy-3-methyl-1-azetidinyl) aniline

A solution of 3-fluoro-4- (3-methoxy-3-methyl-1-azetidinyl) nitrobenzene (1.60 g, 6.7 mmol) in 25% tetrahydrofuran / methanol (35 mL) was degassed by evacuation and filled with N 2 and then treated with 10% palladium / carbon (0.160 g). Ammonium formate (2.10 g, 33.3 mmol) was then added and the degassed mixture one last time. The reaction mixture was stirred at room temperature for 20 minutes, during which time the yellow reaction mixture became colorless. TLC analysis (2: 1 hexane / ethyl acetate) showed the reduction to be complete. The reaction mixture was filtered through Celite (washing with dichloromethane and methanol) and the filtrate was concentrated under vacuum to give a purple gum which was immediately dissolved in 1: 1 acetone / water (30 mL) under N 2. The mixture was cooled with an ice bath at 0 ° C and treated with sodium bicarbonate (1.10 g, 13.4 mmol) and benzyl chloroformate (1.20 g, 1.00 mL, 7.37 mmol) . The cooling bath was allowed to dissipate for a period of 3 h. After stirring another 2 h at room temperature, the reaction mixture was transferred to a separatory funnel with dichloromethane (50 mL). The organic phase was separated, washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to give a purple oil. Chromatography on silica gel, eluting with 6: 1 hexane / ethyl acetate, afforded, after concentration of the appropriate fractions, 2.04 g (89%) of the title compound as a viscous oil which solidified on standing to a solid waxy ether with mp 73-75 ° C and MS (EI) 344 (M +).

Step 4: (R) -3- [3-fluoro-4- (3-methoxy-3-methyl-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methanol

A solution of N- (carbobenzyloxy) -3-fluoro-4- (3-methoxy-3-methyl-1-azetidinyl) aniline (1.85 g, 5.4 mmol) in dry tetrahydrofuran (20 mL) was cooled to -78 ° C with a dry ice / acetone bath and treated with n-butyllithium (3.50 mL

87 111 Ρ 788 498 / ΡΤ 46 of a 1.6 solução solution in hexane, 5.7 mmol) via syringe. After 5 min at this temperature, (R) -glycidyl butyrate (0.823 g, 0.807 mL, 5.7 mmol) was added via syringe and the reaction mixture was left overnight with gradual dissipation of the cooling bath. TLC analysis (5% methanol / chloroform) revealed that the starting derivative Cbz was consumed. The reaction mixture was concentrated under reduced pressure to a waxy orange solid. The residue was dissolved in 20% methanol / dichloromethane, washed sequentially with saturated ammonium chloride, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product. Radial chromatography on silica gel eluting with 2%, 3% and then 5% methanol / chloroform afforded, after concentration of the appropriate fractions, 0.811 g (48%) of the title compound as a colorless gum which was very pure by 1 H NMR analysis. An analytical sample was prepared by recrystallization from dichloromethane / diethyl ether to give a white solid with mp 113-114 ° C and MS (EI) 310 (M +).

Step 5: (R) -β-3-fluoro-4- (3-methoxy-3-methyl-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methanesulfonate

A solution of (R) - [3- [3-fluoro-4- (3-methoxy-3-methyl-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methanol (0.700 g, 2.25 mmol ) in dry dichloromethane (10 mL) was cooled to 0 ° C with an ice bath. Triethylamine (0.250 g, 0.345 mL, 2.48 mmol) and then methanesulfonyl chloride (0.271 g, 0.183 mL, 2.37 mmol) were then added and the reaction stirred under N 2 while the cooling bath dissipated. After 3 h, TLC (5% methanol / chloroform) analysis revealed that the mesylation was practically complete. The reaction mixture was diluted with additional dichloromethane and washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. Chromatography on silica gel, eluting with 3% methanol / chloroform, afforded, after concentration of the appropriate fractions, 0.022 g of recovered starting alcohol and 0.700 g (80%) of the title compound as a white solid with MS (EI) 388 (M +). 47 «7 111 ΕΡ Ο 788 498 / ΡΤ

Step 6: (S) -N- [3- [3-fluoro-4- (3-methoxy-3-methyl-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A mixture of (R) - [[3- [3-fluoro-4- (3-methoxy-3-methyl-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] methanesulfonate (0.680 g, , 75 mmol) in 2: 1 ammonium hydroxide / isopropanol (30 mL) was heated to reflux (dry ice condenser). TLC analysis (5% methanol / chloroform) after 7 hours mainly revealed starting material. The reaction was continued for a further 46 hours. After cooling to room temperature, TLC indicated that the starting mesylate was practically consumed. The reaction mixture was transferred to a separatory funnel along with dichloromethane (100 mL), and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude 5- (aminomethyl) oxazolidinone was dissolved in dry dichloromethane (10 mL), cooled at 0 ° C with an ice bath, and treated with pyridine (0.698 g, 0.708 mL, 8.75 mmol) and acetic anhydride ( 0.357 g, 0.330 mL, 3.50 mmol). The cooling bath was then removed and the reaction stirred at room temperature overnight. The reaction mixture was diluted with additional dichloromethane (60 mL) and washed with 5% aqueous hydrochloric acid, saturated aqueous sodium carbonate, water and brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated under vacuum to give a crude gum. Radiological silica gel eluting with 1%, 2% and 4% methanol / chloroform gave, after concentration of the appropriate fractions, 0.481 g (78%) of the title antibacterial oxazolidinone as a white foamy solid. A lyophilized sample had mp 132-134 ° C and MS (EI) 351 (M +). EXAMPLE 7: (S) -N- [3- (3-fluoro-4- (3-hydroxy-3-methyl-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

Step 1: 3-fluoro-4- (3-hydroxy-3-methyl-1-azetidinyl) nitrobenzene

A solution of 1- (diphenylmethyl) -3-methyl-3-azetidinol hydrochloride (3.00 g, 10.4 mmol) in 2: 1 methanol / tetrahydrofuran (60 mL) was treated with triethylamine (1.00 g, 1.40 mL, 10.4 mmol) and then palladium hydroxide / carbon (0.300 g) under a N 2 stream. The mixture was shaken on a Parr apparatus under 40 psi H2. TLC analysis (hexane / ethyl acetate 2: 1) after 2.5 h showed that the hydrogenolysis was complete. The reaction mixture was filtered through Celite (washing with dichloromethane) and the filtrate concentrated under reduced pressure to give

Which was immediately taken up in dry dimethylsulfoxide (15 ml) and treated with dipotassium hydrogen phosphate (3.40 g, 19.8 mmol) and 3,4-difluoronitrobenzene (1.60 g, 1.10 mL, 9.9 mmol) at ambient temperature under N 2. After 16 hours stirring at this temperature, TLC analysis (2: 1 hexane / ethyl acetate) showed that the reaction was essentially complete. The reaction mixture was transferred to a separatory funnel along with dichloromethane (100 mL) and water (150 mL). After stirring, the organic phase was separated. The aqueous layer was re-extracted with dichloromethane and the combined organic extracts washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. Chromatography on silica gel, eluting with 3: 1 hexane / ethyl acetate, afforded, after concentration of the appropriate fractions, 2.15 g (98%) of the title compound as an orange solid with mp 109-110 ° C and MS (EI) 226 (M +).

Step 2: 4- [3- (tert-butyldimethylsilyl) ox-3-methyl-1-azetidinyl] -3-fluoronitrobenzene

A solution of 3-fluoro-4- (3-hydroxy-3-methyl-1-azetidinyl) nitrobenzene (1.80 g, 8.0 mmol) in dry .delta.-dimethylformamide (15 mL) was cooled to 0 ° C in an ice bath and then treated with imidazole (0.572 g, 8.4 mmol) and tert-butyldimethylsilyl chloride (1.30 g, 8.4 mmol) under N 2. The reaction mixture was stirred overnight with gradual dissipation of the cooling bath. The reaction mixture was then transferred to a separatory funnel along with water and 1: 1 hexane / diethyl ether. After stirring, the layers were separated and the aqueous phase re-extracted with additional 1: 1 hexane / diethyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. Chromatography on silica gel, eluting with 3% diethyl ether / hexane and then 1: 1 hexane / ethyl acetate afforded, after concentration of the appropriate fractions, 0.536 g of the starting alcohol and 1.90 g (70%) of title compound as a bright yellow solid, mp 98-99.5 ° C and MS (EI) 340 (M +).

Step 3: N- (carbobenzyloxy) -4- [3- (tert-butyldimethylsilyl) oxy] -3-methyl-1-azetidinin-3-fluoroaniline

A solution of 2 - [(tert-butyldimethylsilyl) oxy] -3-methyl-1-azetidinyl] -3-fluoronitrobenzene (1.70 g, 5.0 mmol) in methanol / tetrahydrofuran 30 mL) was degassed by repeated evacuation and filling with N2 and then treated with 10% palladium / carbon (0.170 g) under N2. A solid ammonium formate was added, the reaction mixture was degassed one last time, and the mixture was cooled with an ice bath due to the observation of an exotherm. The color of the reaction mixture changed from yellow to colorless. TLC analysis (2: 1 hexane / ethyl acetate) showed the reduction to be complete. The reaction mixture was filtered through Celite® and the filtrate was concentrated under vacuum to give the aniline intermediate as a solid which was immediately dissolved in 1: 1 acetone / water, cooled to 0 ° C with an ice bath, and treated with sodium bicarbonate (0.840 g, 10.0 mmol) and then benzyl chloroformate (0.938 g, 0.785 mL, 5.5 mmol). The reaction mixture was allowed to stir overnight under N 2 with gradual dissipation of the cooling bath. After a total of 16 h, the reaction mixture was transferred to a separatory funnel along with dichloromethane (100 mL). After stirring, the organic phase was separated, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude oil. Chromatography on silica gel, eluting with 9: 1 hexane / ethyl acetate, afforded, after concentration of the appropriate fractions, 1.68 g (76%) of the title compound as a gum with MS (EI) 444 ( M +).

Step 4: (R) -3- [4- (3-Butyldimethylsilyl)] - 3-methyl-1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methanol

A solution of N- (carbobenzyloxy) -4- [3 - ((tert -butyldimethylsilyl) oxy] -3-methyl-1-azetidinyl] -3-fluoroaniline (1.60 g, 3.8 mmol) in tetrahydrofuran (20 mL) under N 2 was cooled to -78 ° C with a dry ice / acetone bath and treated with n-butyllithium (2.40 mL of a 1.55 M solution in hexane, 3.8 mmol) (0.548 g, 0.538 mL, 3.8 mmol) was added. After the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm to After 2 h at this temperature, TLC analysis (2: 1 hexane / ethyl acetate) showed that the starting derivative Cbz had been consumed. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product.Chromatography on silica gel, eluting with 30% ethyl acetate / dichloride (1.10 g, 71%) of the title 5- (hydroxymethyl) oxazolidinone gave a white solid, mp 143.5-144.5 ° C and MS (EI) 410 (M +).

87 111 ΕΡ Ο 788 498 / ΡΤ

Step 5: (R) 344 - [3- (tert-butyldimethylsilyl) oxyl-3-methyl-1-azetidinyl-3-fluoro-phenyl] -2-oxo-5-oxazolidinyl] methyl] methanesulfonate

A solution of (R) - [3- [4- [3 - [(tert-butyldimethylsilyl) oxy] -3-methyl-1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] , 0.003 g, 2.43 mmol) in dry dichloromethane (15 mL) was cooled to 0 ° C with an ice bath and treated with triethylamine (0.295 g, 0.406 mL, 2.92 mmol) and then with methanesulfonyl chloride (0.321 g, 0.217 mL, 2.80 mmol) under N 2. After 2 h at 0 ° C, TLC analysis (5% methanol / chloroform) revealed that the reaction was complete. The reaction mixture was transferred to a separatory funnel along with more dichloromethane (75 mL). The organic layer was washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate, filtered and concentrated under vacuum to give 1.03 g (94%) of the title compound as a white solid. white solid, mp 113-115 ° C and MS (EI) 488 (M +).

Step 6: (R) -3-3- [3- (tert-butyldimethylsilyl) oxy] -3-methyl-1-azetidinin-3-fluoro-phenyl] -2-oxo-5-oxazolidinyl] methyl] azazide

A solution of (R) - [[3- [4- [3 - [(tert-butyldimethylsilyl) oxy] -3-methyl-1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] in dry N, N-dimethylformamide (20 mL) under N 2 was treated with sodium azide (0.273 g, 4.2 mmol) at ambient temperature. The reaction mixture was heated at 70 ° C for 3 h and then cooled to room temperature. TLC analysis (5% methanol / chloroform) at this time revealed that the reaction was complete. The solvent was removed in vacuo and the residue taken up in dichloromethane (100 mL) and water. The organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo to give 0.820 g (90%) of the title compound as a white solid with mp 127-128øC and MS (EI) 435 ( M +).

Step 7: (S) -N- [3- [4- (tert-butyldimethylsilynoxy] -3-methyl-1-azetidinyl] -3-fluoro-phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A solution of (R) - [[3- [4- [3 - [(tert-butyldimethylsilyl) oxy] -3-methyl-1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] azide (0.750 g, 1.72 mmol) in ethyl acetate (20 mL) was degassed by repeated evacuation and filling with N2. The solution was then treated with 10% palladium / carbon (0.075 g) under a stream of N 2. The atmosphere was replaced by H2 (flask) by evacuation and repeated filling and the reaction mixture was stirred at room temperature. TLC analysis (5% methanol / chloroform) after 6 h showed the reduction to be complete. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was dissolved in dry dichloromethane (10 mL), cooled at 0 ° C with an ice bath, and treated with pyridine (0.680 g, 0.666 mL, 8.60 mmol) and acetic anhydride (0.263 g, 0.243 mL, , 58 mmol). The cooling bath was removed and the reaction stirred at room temperature under N 2. After 3 h, the reaction mixture was transferred to a separatory funnel along with dichloromethane (100 mL). The mixture was washed with 10% hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under vacuum. Radial chromatography on silica gel, eluting with 3% and then 5% methanol / chloroform, afforded, after concentration of the appropriate fractions, 0.643 g (83%) of the title compound as a white solid with mp 137-138 ° C and MS (EI) 451 (M +).

Step 8: (S) -N- [3- (3-fluoro-4- (3-hydroxy-3-methyl-1-azetidinyl) phenyl] -2-oxo-5-oxazolidinyl] methylacetamide

A solution of (S) -N - [[3- [4- [3 - [(tert-butyldimethylsilyl) oxy] -3-methyl-1-azetidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (0.550 g, 1.22 mmol) in acetonitrile (20 mL) in a polypropylene bottle was treated with 40% aqueous hydrofluoric acid (5 mL) at ambient temperature. After 16 h. TLC analysis (5% methanol / chloroform) showed that the deprotection was essentially complete. The reaction mixture was transferred to an Erlenmeyer flask along with some dichloromethane (150 mL). The stirred mixture was carefully treated with aqueous saturated sodium carbonate (300 mL, gas evolution). After gas evolution ceased, the mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was neutralized to pH 7 by the addition of 6N hydrochloric acid and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under vacuum. Radiological chromatography on silica gel, eluting with 5% methanol / chloroform, afforded, after concentration of the appropriate fractions, 0.374 g (91%) of the title antibacterial oxazolidinone agent as a white solid with mp 152-153øC and MS (EI) 337 (M +). 52 87 111 ΕΡ Ο 788 498 / ΡΤ

Examples of Pyrrolidinyl Phenyloxazolidinones EXAMPLE 8: (S) -N-Aza-5,5-dimethyl-4,6-dioxabicyclo [3.3.0] octan-1-yl) -3-fluorophenyl-2-oxo-5-oxazolidinylmethyl] acetamide: 3-Fluoro -1-nitro-4- (2,5-dihydropyrrole) benzene:

A solution of 2.30 g (14.47 mmol) of 2,4-dinitrofluorobenzene and 5.04 g (28.93 mmol) of dibasic potassium phosphate in 30 mL of DMSO was treated with 1.0 g (14.47 mmol) of 3-pyrroline , followed by heating at 60 ° C for 24h. The solution was cooled and diluted with 100 mL of chloroform followed by extraction with water (5x75 mL). Drying (Na2 SO4) and concentration in vacuo afforded a yellow solid which was recrystallized from hot ethyl acetate-hexane to provide 2.58 g (86%) of the title compound as yellow prisms, m.p. 132-134 ° C. 3-Fluoro-1-nitro-4- (cis-3,4-dihydroxypyrrolidinyl) benzene:

A solution of 1.25 g (6.02 mmol) of the previous compound and 881 mg (7.52 mmol) of N-methylmorpholine N-oxide in 60 mL of acetone and 13 mL of water was treated with 4 mL of a 2.5% of osmium tetroxide in tert-butyl alcohol followed by stirring at room temperature for 24h. The solution with 500mg of sodium bisulfite, 2g of magnesol, and 10ml of water followed by stirring for 20min. The mixture was filtered through celite, washing the filter cake with acetone. The filtrate was concentrated in vacuo and diluted with 100mL of ethyl acetate and 150mL of water. The aqueous layer was extracted with ethyl acetate (3x100mL) and the combined organic layers were dried (Na2 SO4) and concentrated in vacuo to give a yellow solid. This material was recrystallized from hot acetone-hexane to give 1.33 g (91%) of the title compound as a yellow solid, m.p. 151-153 ° C. 1-M-aza-5,5-dimethyl-4,6-dioxabicyclo3.3.01octan-1-yl) -2-fluoro-4-nitrobenzene (3):

A solution of 1.27 g (5.24 mmol) of the above diol in 10 mL of dimethylformamide was treated with 1.09 g (1.3 mL, 10.49 mmol) of 2,2-dimethoxypropane and a few crystals of p-toluenesulfonic acid followed by stirring at room temperature for 24h. The solution was diluted with 50mL of

87 111 ΕΡ Ο 788 498 / ΡΤ 53 chloroform and extracted with water (5x30mL). Drying (Na2 SO4) and concentration in vacuo gave 1.45 g (98%) of the title compound as a yellow solid, pure enough for later use. An analytical sample was obtained by recrystallization from hot acetone-hexane, m.p. 113-114 ° C. 1-aza-5,5-dimethyl-4,6-dioxabicyclo3.3.01octan-1-ol-2-fluoro-4- (phenylmethoxycarbonylaminobenzene:

A solution of 1.45g (5.14mmol) of the previous compound in 50mL of tetrahydrofuran was treated with 260mg of 10% palladium on carbon followed by hydrogenation under an atmosphere for 3h. The reaction vessel was purged with nitrogen and treated with 20mL of saturated sodium bicarbonate solution followed by cooling to 0 ° C and addition of 1.75g (1.47mL, 10.27mmol) of benzyl chloroformate. The solution was stirred at 0 ° C for 30 min followed by heating to ambient temperature for 18h. The mixture was diluted with 50 mL of ethyl acetate and 50 mL of water and filtered through celite, washing the filter cake with ethyl acetate. The filtrate layers were separated and the organic phase was extracted with 50 ml of water and 50 ml of saturated sodium chloride solution. Drying (Na 2 SO 4) and concentration in vacuo afforded a light purple solid which was recrystallized from hot ethyl acetate-hexane to provide 1.56 g (79%) of the title compound as fine white crystals. 1 H NMR (CDCl 3): δ 7.39, 7.25, 6.93, 6.67, 5.19, 4.80, 3.73, 2.97, 1.53, 1.37. (5): â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (R) -3-

A solution of 1.36 g (3.52 mmol) of the Cbz derivative of the previous compound in 48 mL of tetrahydrofuran at -78 ° C was treated dropwise with 2.41 mL (1.6M, 3.87 mmol) of n- butyllithium in hexane, followed by stirring at -78 ° C for 30 min. The solution was then treated with 558mg (0.55ml, 3.87mmol) of pure (R) - (+) - glycidyl butyrate followed by heating at 0øC for 30min and then to ambient temperature for 18hr. The solution was then cooled to 0 ° C and treated with 4mL of saturated aqueous ammonium chloride solution, followed by dilution with 200mL of dichloromethane and extraction with water (2 x 50mL) and saturated ammonium chloride solution (50ml). Drying (Na 2 SO 4) and concentration in vacuo gave the brown solid which was chromatographed on 80g of 230-400 mesh silica gel, eluting with 2% (v / v) methanol in dichloromethane.

87 111 ΕΡ Ο 788 498 / ΡΤ 54

These procedures gave 840mg of the title compound as an off-white solid. ¹ NMR (CDCl 3): δ 7.34, 7.06, 6.71, 4.80, 4.75, 4.01, 3.73, 3.67, 3.56, 2.95, 1.50 , 1.36. (SH3- (4- (1-Aza-5,5-dimethyl-4,6-dioxabicyclo3.3.01octan-1-yl) -3-fluorophenyl-2-oxo-5-oxazolidinylmethyl) methanesulfonate:

A solution of 791 mg (2.25 mmol) of the above alcohol and 283 mg (0.39 mL, 2.81 mmol) of triethylamine in 11 mL of dichloromethane at 0 ° C was treated with 296 mg (0.20 mL, 2.58 mmol) of of methanesulfonyl chloride, followed by stirring at 0 ° C for 30 min. The mixture was warmed to room temperature and diluted with 75 ml of dichloromethane followed by extraction with water (2 x 30 ml) and saturated sodium bicarbonate solution (30 ml). Drying (Na 2 SO 4) and concentration in vacuo gave 810mg (84%) of the title mesylate as a sufficiently pure white-dirty solid for further use. 1 H NMR (CDCl 3): δ 7.36, 7.07, 6.73, 4.90, 4.82, 4.48, 4.41, 4.10, 3.89, 3.77, 3.10 , 3.02,1,51,1,37. (S) -N-3- [4- (1-Aza-5,5-dimethyl-4,6-dioxabicyclo3.3.01octan-1-yl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide:

A solution of 810mg (1.88mmol) of the above mesylate in 8mL of tetrahydrofuran-1: 1 isopropyl alcohol in a re-sealable thick wall tube was treated with 8mL of ammonium hydroxide. The tube was sealed and heated at 100 ° C for 22h. The tube was cooled and the reaction mixture partitioned between chloroform and water. The organic layer was dried (Na 2 SO 4) and concentrated in vacuo to give 520mg of a tan colored solid which was dissolved in 2mL of pyridine and treated with 357mg (0.33mL, 3.50mmol) of acetic anhydride followed by stirring at at room temperature for 18h. The solution was diluted with chloroform (20mL) and extracted with water (4 x 20mL). The organic layer was dried (Na2 SO4) and concentrated in vacuo and the obtained solid recrystallized from chloroform-hexane to provide 350mg (59%) of the title acetamide as off-white needles, m.p. 195-7 ° C. EXAMPLE 9: (S) -N- [3- [4- (3,4-cis-dihydroxypyrrolidinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (9).

A solution of 249mg (0.63mmol) of the compound prepared in Example 8 in 2mL of tetrahydrofuran was treated with 2mL of 2N hydrochloric acid solution, followed by stirring at room temperature for 18h. The mixture was concentrated in vacuo and the residue treated with 30mL of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (2 x 50 mL), dried (Na 2 SO 4) and concentrated in vacuo to give 110 mg of an off-white solid.

This material was subjected to radial chromatography on a 2mm chromatotron plate eluting with 7% (v / v) methanol in dichloromethane. These procedures gave 60mg (28%) of the title diol as a white solid, m.p. 183-189 ° C (decomposition). EXAMPLE 10 3-Fluoro-4- (3-hydroxypyrrolidininnitrobenzene) To a solution of 3-pyrrolidinol (1-hydroxyethyl) -2-oxo-3-oxazolidinylmethylacetamide (3.0 g) in dimethylformamide (30 ml) was added potassium carbonate (3.94 g) The mixture was stirred at room temperature overnight and then filtered, followed by The residue obtained was chromatographed on a silica gel column eluting with ethyl acetate / hexane with an increasing content of ethyl acetate (50% to 60%) The appropriate fractions were washed with dichloromethane. (4.83 g); 1 H NMR (CD 3 OD, 270 MHz), δ 0.85 (2H, m), 2.25-2.57 (4H, m) , 3.26 (1H, m), 5.47 (1H, t, J = 8.6Hz), 6.62 (1H, dd, J = 2.4, 14.0Hz), 6.69 (1H, 1H, dd, J = 2.4, 8.6 Hz) 3-Fluoro-4- (3-tert-butyldimethylsilyloxy) pyrrolidininnitrobenzene:

A mixture of the above compound (4.83 g), triethylamine (9.5 ml) and dimethylaminopyridine (2.79 g) in tetrahydrofuran (100 ml) was treated with tert-butyldimethylsilyl chloride (5.15 g) at 0 ° C. and stirred at room temp. for 2 days. THE

The mixture was filtered and the insoluble material was washed with dichloromethane. The combined filtrate was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on a silica gel column eluting with ethyl acetate / hexane (70/30). The appropriate fractions were combined and concentrated under reduced pressure to give the title compound (11) (6.45 g); ¹ NMR (CDCl 3), δ 0.09 (6H, s), 0.88 (9H, s), 2.02 (2H, m), 3.42-3.78 (4H, m). 4.52 (1H, m). 6.53 (1H, t, J = 8.9 Hz). 7.87 (1H, dd, J = 2.4, 14.0 Hz). 7.94 (1H, dd, J = 2.4, 8.9 Hz). 3-Fluoro-4- (3-tert-butyldimethylsilyloxy) pyrrolidinyl] aniline:

Palladium on carbon (10%, 500 mg) was added to a mixture of the previous compound (5.0 g) in a mixed solvent of dichloromethane (20 ml) and methanol (100 ml). The mixture was stirred under 1 atmosphere of hydrogen for 6 h, then filtered and the palladium on carbon was washed with methanol and dichloromethane. The combined filtrates were concentrated under reduced pressure to give the title compound (4.52 g); 1 H NMR (CDCl 3), δ0.08 (6H, s), 0.88 (9H, s), 1.87 (1H, m), 2.11 (1H, m), 3.05 (1H, m), 4.48 (1H, m), 6.38 (1H, dd, J = 2.4, 8.9 Hz), 6.30 , 44 (1H, dd, J = 2.4, 14.0Hz), 6.61 (1H, t, J = 8.9Hz). 1-Benzyloxycarbonylamino-4- [3- (tert-butyldimethylsilyloxypyrrolidinyl] -3-fluorobenzene:

Benzyl chloroformate (3.0 ml) was added to a mixture of the previous compound (4.52 g) and sodium bicarbonate (1.76 g) in tetrahydrofuran (50 ml) at 0 ° C. The mixture was stirred at room temperature overnight and then filtered followed by washing with tetrahydrofuran. The combined filtrates were dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to a silica gel column eluting with hexane / ethyl acetate (90/10). The appropriate fractions were combined and concentrated under reduced pressure to give the title compound (4.40 g); ¹H NMR (CDCl3), δ0.08 (6H, s), 0.88 (9H, s), 1.87 (1H, m), 2.11 (1H, m), 3.05 (1H, m (2H, s), 6.59 (1H, t, J = 8, 1H) 9Hz), 6.88 (1H, dd, J = 2.4, 8.9Hz), 7.10 (1H, dd, J = 2.4, 14.0Hz), 7.36 (5H, m). 87 111 ΕΡ Ο 788 498 / ΡΤ 57

(S) 3- [4- [3- (tert-butyldimethylsilyloxy) pyrrolidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methanol:

A solution of the above compound (4.40 g) in dry tetrahydrofuran (50 ml) was cooled to -78 ° C under nitrogen and treated with n-BuLi (7.3 ml, 1.6M in hexane) with stirring for 5 min. The mixture was treated with 1.65 ml of (R) - (+) glycidyl butyrate and allowed to warm slowly to ambient temperature overnight. The reaction was quenched by addition of saturated ammonium sulfate solution (10 mL) and the mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on a silica gel column eluting with hexane / ethyl acetate with increasing content in ethyl acetate (50% to 70%). The appropriate fractions were pooled and concentrated under reduced pressure to give the title compound (1.44 g); 1 H NMR (CDCl 3), δ0.08 (6H, s), 0.88 (9H, s), 1.91-2.10 (2H, m), 3.18 (1H, m), 3.39- 3.48 (1H, m), 3.87 (1H, m), 3.87-4.01 (3H, m), 4.48 (1H, , 6.66 (1H, t, J = 9.5Hz), 7.04 (1H, dd, J = 2.4, 9.5Hz), 7.32 (1H, dd, J = 2.4, 14.6 Hz). (S) - [3- [4- [3-tert-butyldimethylsilyloxy] pyrrolidin-3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] methanesulfonate:

To a solution of the previous compound (1.44 g) in pyridine (10 ml) was added p-toluenesulfonyl chloride (0.88 g) at 0 ° C with stirring. The mixture was stirred at room temp. atmosphere at night. Water (40 ml) was slowly added to the mixture with stirring and the mixture was further stirred for 1 h to give crystals. The crystals were collected by filtration, washed with water and dried at 40 ° C under reduced pressure overnight to give the title compound (1.96 g); 1 H NMR (CDCl 3), δ 0.09 (6H, s), 0.88 (9H, s), 1.90-2.08 (2H, m), 2.46 (3H, s), 3.21 (1H, m), 3.40-3.49 (2H, m), 3.65 (1H, m), 3.81 (1H, dd, J = 5.9, 8.9 Hz) J = 8.9Hz), 4.24 (2H, m), 4.49 (1H, m), 4.80 (1H, m), 6.63 (1H, t, J = 9.5 Hz), 6.96 (1H, dd, J = 2.4, 9.5 Hz), 7.23 (1H, dd, J = 2.4, 14.6 Hz), 7.36 (2H, d, J = 7.8Hz), 7.79 (2H, d, J = 7.8Hz). 58 58

(S) -N- [3- [4- [3- (tert-butyldimethylsilyloxy) pyrrolidin-3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide;

A mixture of the previous compound (1.96 g) in dimethylformamide (20 ml) was treated with sodium azide (455 mg) and heated at 60 ° C overnight. After cooling to room temperature, the mixture was filtered and the precipitate was washed with dichloromethane. The combined filtrates were concentrated under reduced pressure. The residue obtained was chromatographed on a silica gel column eluting with hexane / acetone (80/20). The appropriate fractions were combined and concentrated under reduced pressure to give a compound (1.40 g). A solution of this compound in dry tetrahydrofuran (20 ml) was treated with triphenylphosphine (868 mg) and stirred at room temp. for 2 h. The mixture was treated with water (0.5 ml) and stirred at 40 ° C for 4 h, then at room temperature overnight. The mixture was concentrated under reduced pressure and dried by azeotropic evaporation with toluene. The residue obtained was suspended in dichloromethane (20 ml) and treated with pyridine (0.5 ml) and acetic anhydride (0.6 ml) at 0 ° C. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was subjected to a silica gel column eluting with methanol / dichloromethane increasing in methanol (1% to 3%). The appropriate fractions were pooled and concentrated under reduced pressure to give the title compound (1.502 g); 1 H NMR (CDCl 3), δ0.08 (6H, s), 0.88 (9H, s), 1.89-2.09 (2H, m), 2.02 (3H, s), 3.18 (1H, m), 3.36-3.67 (6H, m), 3.71 (1H, dd, J = 6.8, 8.9Hz), 3.99 (1H, t, J = 8). (1H, m, J = 9.2 Hz), 4.61 (1H, m), 4.76 (1H, m), 6.20 (1H, broad, NH), 6.61 (1H, 6.98 (1H, dd, J = 2.4, 9.2Hz), 7.30 (1H, dd, J = 2.4, 15.1Hz). (S) -N- [3- (4- (3-hydroxypyrrolidinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinylmethyl] acetamide:

A mixture of the previous compound (1.50 g) in dry tetrahydrofuran (8 ml) was treated with tetrabutylammonium fluoride (6.7 ml, 1.0 M in tetrahydrofuran) at 0 ° C and was allowed to warm to temp. with stirring for 4 h. The mixture was treated with water (50 ml) and extracted with dichloromethane (30 ml x 4). The unified organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to a silica gel column eluting with acetone / hexane (80/20). The appropriate fractions were combined and concentrated under reduced pressure to give the title compound (0.77 g); 1 H NMR (DMSOd 6), δ 1.78-2.00 (2H, m), 1.80 (3H, s), 3.12 (1H, m), 3.26-

(1H, t, J = 8.9 Hz), 4.04 (5H, m), 3.67 (1H, 9H), 4.34 (1H, m), 4.68 (1H, m), 4.91 (1H, d, J = 4.1Hz, OH) 9.7 Hz), 7.08 (1H, dd, J = 2.4, 9.7 Hz), 7.38 (1H, dd, J = 2.4, 16.2 Hz), 8.23 (1H, 1H, t, J = 5.7 Hz, NH). EXAMPLE 11 7-Benzyl-7-aza-1,4-dioxaspiro (4.5) nonane: To a suspension of 4-chloro-4- (1.92 g) and ethylene glycol (6.81 g) in benzene (70 ml) was added p-toluenesulfonic acid monohydrate (1.93 g). refluxed with azeotropic water removal by means of a Dean Stark trap for 6 h After cooling to room temperature the mixture was washed with satd sodium bicarbonate (50 ml x 3) The aqueous layer was then extracted with dichloromethane The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.57 g); 1 H NMR (CDCl 3), δ 2.06 (2H J = 7.3Hz), 2.64 (2H, s), 2.66 (2H, t, J = 7.3Hz), 3.61 (2H, s), 3.89 (4H , m), 7.28 (5H, m). 7-Aza-1,4-dioxaspiro (4.5) nonane.

Palladium hydroxide on carbon (20%, 200 mg) was added to a solution of the previous compound (1.57 g) in a mixed solvent of dichloromethane (10 ml) and methanol (20 ml). The mixture was stirred under 3kgf / cm 2 of hydrogen for 2 days, then filtered and the palladium hydroxide on carbon washed with methanol and dichloromethane. The combined filtrate was concentrated under reduced pressure to give the title compound (1.38 g); Δ 2.17 (2H, t, J = 7.3Hz), 3.35 (2H, s), 3.52 (2H, t, J = 7.3Hz) 99 (4H, s). 4- (7-Aza-1,4-dioxaspiro (4.5) nonan-7-yn-3-fluoronitrobenzene:

Following the general procedure of Example 9 and making non-critical variations but starting from the previous compound (1.38 g), the title compound (1.50 g) was obtained, ¹ NMR (CDCl 3), δ 2.18 (2H J = 7.3Hz), 3.67 (2H, s), 3.72 (2H, t, J = 7.3Hz), 4.02 (4H, s), 6.53 (1H , 7.88 (1H, dd, J = 2.4, 14.0 Hz), 7.94 (1H, dd, J = 2.4, 8.9 Hz) .

(4.5) nonan-7-yn-3-fluoro-1- (phenylmethoxycarbonylamino) -benzene: (1R) -1-

Following the general procedure of Example 9 and making non-critical variations but starting from the previous compound (1.49 g), the title compound (2.44 g), 1 H NMR (CDCl 3), δ 2.16 (2H J = 6.8 Hz). 3.41 (2H, t, J = 6.8 Hz). (2H, s), 6.60 (1H, t, J = 9.2Hz), 6.91 (1H, dd, J = 2.4, 9.2 Hz), 7.22 (1H, dd, J = 2.4, 14.0 Hz), 7.37 (5H, m). (R) - (3- (3-fluoro-4- (7-aza-1,4-dioxasnero (4.5) nonan-7-yl) phenyl) -2-oxo-5-oxazolidinylmethanol:

A solution of the above compound (2.44 g) in dry dimethylformamide (25 ml) was cooled to -78 ° C under nitrogen and treated with bis (trimethylsilyl) amide (6.6 ml, 1.0M in tetrahydrofuran) with stirring for 5 min. The mixture was treated with 0.93 mL of (R) - (-) - glycidyl butyrate and allowed to slowly warm to room temp. during the night. A small excess of lithium bis (trimethylsilyl) amide was quenched by addition of water (5 ml). The mixture was concentrated under reduced pressure and dried by azeotropic evaporation with toluene. The residue was suspended in dichloromethane (100 ml) and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure and the obtained residue was then subjected to a silica gel column eluting with hexane / acetone (50/50). The appropriate fractions were pooled and concentrated under reduced pressure to give the title compound (1.79 g); 1 H NMR (DMSOd 6), δ 2.07 (2H, t, J = 7.3Hz), 3.35 (4H, superimposed with signals due to solvent), 3.50-3.69 (2H, m ), 3.78 (1H, dd, J = 7.3, 9.2Hz), 3.92 (4H, s), 4.02 (1H, t, J = 9.2Hz), 4.67 (1H (1H, t, J = 5.9Hz, OH), 6.77 (1H, t, J = 10.3Hz), 7.13 (1H, dd, J = 4, 10.3Hz), 7.46 (1H, dd, J = 2.4, 16.2Hz). (R) -N - ((3- (3-fluoro-4- (7-aza-1,4-dioxaspiro (4.5) nonan-7-yl) phenyl) -2-oxo-5-oxazolidinylmethanazide:

Following the general procedure of Example 9 and making non-critical variations but starting from the previous compound (1.78 g), the title compound (1.76 g), 1 H NMR (CDCl 3), δ 2.14 (2H J = 7.3Hz), 2.44 (3H, s), 3.45 (2H, t, J = 7.3Hz), 3.49 (2H, s), 3.73-4 , 13 (2H, m), 3.98 (4H, s), 4.24 (2H, m), 4.80 (1H, m), 6.60

(1H, dd, J = 2.4, 9.5Hz), 7.23 (1H, dd, J = 9.5Hz), 6.96 (1H, dd, , 2.4, 14.6Hz), 7.36 (2H, d, J = 7.8Hz), 7.78 (2H, d, J = 7.8Hz). (4.5) nonan-7-yl) phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide: â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡

Following the general procedure of Example 9 and making non-critical variations, Lindlar catalyst (150 mg) was then added to a mixture of the previous compound (17) (1.45 g) in a mixed solvent of dichloromethane (10 ml) and methanol ( 40 ml). The mixture was stirred under a pressure. atmospheric hydrogen for 2 days, then filtered and the catalyst washed with methanol and dichloromethane. The combined filtrate was concentrated under reduced pressure. The residue obtained was suspended in dichloromethane (20 ml) and treated with pyridine (0.3 ml) and acetic anhydride (0.7 ml) at 0 ° C. The mixture was stirred at room temp. overnight and concentrated under reduced pressure. The residue was subjected to a silica gel column eluting with methanol / dichloromethane increasing in methanol (2% to 5%). The appropriate fractions were pooled and concentrated under reduced pressure to give the title compound (0.72 g); 1 H NMR (CDCl 3), δ 2.01 (3H, s), 2.16 (2H, t, J = 7.3Hz), 3.43 (2H, t, J = 7.3Hz) (2H, m), 3.71 (1H, dd, J = 6.8, 9.2Hz), 3.98 (5H, m), 4 (1H, dd, J = 2.4, 9.2 Hz), 6.75 (1H, d, J = Hz), 7.33 (1H, dd, J = 2.4, 15.1 Hz). (S) -N - ((3- (3-fluoro-4- (3-oxopyrrolidinyl) phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide:

A mixture of the above compound (610 mg) in acetone (12 ml) and water (3.7 ml) was treated with p-toluenesulfonic acid monohydrate (609 mg) and refluxed for 3 hours. After cooling to room temp. The mixture was concentrated under reduced pressure. The residue was treated with 5 ml of triethylamine and extracted with dichloromethane (30 ml x 5). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to a silica gel column eluting with hexane / acetone (50/50). The appropriate fractions were combined and concentrated under reduced pressure to give the title compound (390 mg); 1 H NMR (CDCl 3, δ 2.03 (3H, s), 2.65 (2H, t, J = 6.8Hz), 3.47-3.78 (7H, m), 4.02 (1H, J = 8.9Hz), 4.76 (1H, m), 6.18 (1H, t, J = 5.9Hz, NH), 6.77 (1H, t, J = 9.2 Hz), 7.09 (1H, dd, J = 2.4, 9.2Hz), 7.43 (1H, dd, J = 2.4,15.1Hz) 62 87 111 ΕΡ Ο 788 498 EXAMPLE 12 (S) -N - ((3- (3-Fluoro-4- (3- (phenylmethoxyacetylamino) -oquinolyl) phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide

Step 1: 3-Fluoro-1-nitro-4- (3-trifluoroacetylamino) pyrrolidinylbenzene

A solution of 4.49 g (20.54 mmol) of 3- (trifluoroacetylamino) pyrrolidine hydrochloride and 2.97 g (18.68 mmol) of 3,4-difluoronitrobenzene and 7.16 g (41.10 mmol) of dibasic potassium phosphate in 87mL of DMSO was heated at 90 ° C for 18h. The mixture was cooled and diluted with 300 mL of ethyl acetate. The solution was extracted with water (5 x 100 mL) and dried (Na2 SO4). Concentration in vacuo afforded a yellow solid which was recrystallized from hot ethyl acetate-hexane to afford 5.0 g (84%) of the title product as a yellow crystalline solid, m.p. 165-167 ° C.

Step 2: 3-Fluoro-1- (phenylmethoxycarbonyl) amino-4- (3-trifluoroacetylamino) pyrrolidinylbenzene

A solution of 4.10 g (12.76 mmol) of the nitro compound in 100 mL of ethyl acetate was treated with 500 mg of 10% palladium on carbon followed by hydrogenation at atmospheric pressure for 4 hours. The mixture was filtered through celite, washing the filter cake with ethyl acetate. The filtrate was concentrated in vacuo and the residue was dissolved in 50mL of acetone and treated with 75mL saturated NaHC03 solution followed by cooling to 0Â ° C and treatment with 4.36g (3.64mL, 25.53mmol) of benzyl chloroformate . The solution was then warmed to room temperature for 18h. The mixture was diluted with 200 ml of ethyl acetate and extracted with water (2 x 50 ml) followed by drying (Na 2 SO 4). Concentration in vacuo afforded a beige solid which was recrystallized from hot ethyl acetate-hexane to provide 4.41 g (81%) of the title derivative Cbz as light beige needles, m.p. 143-145 ° C.

Step 3: 3-Fluoro-1- (phenylmethoxycarbonyl) amino-4- (3- (1,3-dimethylhexahydro-2-oxo-1,35-triazin-5-yl) pyrrolidinyl) benzene

A solution of 1.86 g (4.37 mmol) of the derivative Cbz in 36 mL of THF was treated with 50 mL of 2N NaOH solution followed by heating under reflux for 36 h. The solution was cooled and diluted with 50mL of water followed by extraction with ethyl acetate (4 x 75mL). The combined organic layers 87 111 ΕΡ Ο 788 498 / ΡΤ 63

were extracted with saturated NaCl solution followed by drying (Na 2 SO 4) and concentration in vacuo. The obtained amber oil was dissolved in 20 ml of dioxane and 40 ml of toluene and the resulting solution was treated with 385 mg (4.37 mmol) of N, N'-dimethylurea and 5 ml of 37% aqueous formaldehyde solution. The mixture was heated at reflux to ca. of 5 ml of water was collected in a Dean-Stark trap. The solution was cooled and concentrated in vacuo. The residue was chromatographed on 180g of 230-400 mesh silica gel, eluting with 2% (v / v) methanol in dichloromethane. These procedures gave 1.40 g (73%) of the title product as fine white crystals, m.p. 192-194 ° C.

Step 4: (R) - (3- (3-Fluoro-4- (3- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) pyrrolidinophenyl) -2-oxo-5-oxazolidinemethanol

A solution of .737mg (1.67mmol) of the triazone in 10mL of DMF at -50Â ° C was treated with 1.84mL (1.84mmol) of lithium hexamethyldisilazide in THF. The solution was stirred at -50 ° C for 5min, followed by addition of 265mg (0.26mL, 1.84mmol) of (R) - (+) - glycidyl butyrate. The solution was then warmed to room temperature for 18h. The mixture was concentrated under vacuum (ca 0.3mmHg) and the residue was chromatographed over 36g silica gel 230-400mesh, eluting with 3% (v / v) methanol in dichloromethane. These procedures gave 400mg (59%) of the title product as a white solid. 1 H NMR (CDCl 3): δ 7.36, 7.05, 6.65, 4.72, 4.27, 4.18, 3.95, 3.77, 3.46, 2.88, 2.17 , 1.94.

Step 5: (R) - (3- (3-Fluoro-4- (3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-ylpyrrolidinophenyl) -2-oxo-5-oxazolidinylmethanesulfonate

A solution of 395mg (0.97mmol) of the oxazolidinone, and 146mg (0.20mL, 1.45mmol) of triethylamine in 5mL of dichloromethane at 0 ° C was treated with 471mg (0.32mL) of methanesulfonyl chloride. The solution was stirred at 0 ° C for 30 minutes, followed by warming to room temperature. The solution was treated with water and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried (Na2 SO4) and concentrated in vacuo to give 460mg (98%) of the title product as an off-white solid suitable for use in the next step. ¹ NMR (CDCl 3): δ 7.33, 7.03, 6.63, 4.89, 4.45,

64 87 111 ΕΡ Ο 788 498 / ΡΤ

Step 6: (S) -N - ((3- (3-Fluoro-4- (3- (phenylmethoxyacetylamino) pyrrolidinophenyl) -2-oxo-5-oxazolidinylmethyl) acetamide

A solution of 460mg (0.97mmol) of the mesylate in 15ml of isopropyl alcohol and 15ml of ammonium hydroxide in a sealed tube was heated at 100 ° C for 18 hours. The mixture was cooled and diluted with water followed by extraction with chloroform. The organic layer was dried (Na2 SO4) and concentrated in vacuo. The residue was dissolved in 4 ml of pyridine and treated with 0.5 ml of acetic anhydride followed by stirring at room temperature for 18 hours. The mixture was concentrated in vacuo to give an oil which was dissolved in chloroform and extracted with water. The organic layer was dried (Na2 SO4) and concentrated in vacuo to give 472 mg of the acetamide derivative, which was directly dissolved in 4 mL of 1N HCl solution followed by stirring at room temperature for 18 hours. The mixture was concentrated in vacuo and dissolved in 4mL of acetone and treated with 2mL of saturated NaHCO 3 solution followed by treatment with benzylacetyl chloride (217mg, 0.14mL, 1.18mmol) followed by stirring at room temperature for 1h. The mixture was concentrated in vacuo and the residue was chromatographed on 25g of 230-400 mesh silica gel, eluting with 2% (v / v) methanol in dichloromethane and then with 3% (v / v) methanol in dichloromethane . These procedures gave 189 mg (40%) product of benzyloxyacetamide as a white solid. 1 H NMR (CDCl 3): δ 7.33, 7.02, 6.81, 6.68, 6.08, 4.75, 4.60, 4.01,3,71,3,61, 3.34 , 2.32, 2.02, 1.91. EXAMPLE 13: (NÎ ± - ((3- (3-Fluoro-4- (3- (hydroxyacetylamino) pyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] acetamide

Continuing from the procedure of Example 12, Step 6, a solution of 189mg (0.39mmol) of benzyloxyacetamide in 5mL of methanol and 5mL of THF was treated with 200mg of 10% palladium on carbon followed by hydrogenation at atmospheric pressure for 1h. The solution was diluted with methanol and filtered through celite, washing the filter cake with methanol. The filtrate was concentrated in vacuo to give an oil, which was chromatographed on 10g of 230-400 mesh silica gel, eluting with 7% (v / v) methanol in dichloromethane. These procedures gave 95 mg (62%) of the hydroxyacetamide derivative as a pink solid. 1 H NMR (CDCl 3): 57.41, 7.10, 6.78, 4.77, 4.53, 4.10, 4.00, 3.77, 3.57, 3.32, 2.30, 1.99, 1.98. EXAMPLE 14 (S) -N- [3-Fluoro-4- (cis -3- (methoxycarbonylamino) -4-methylpyrrolidinophenyl] -2-oxo-5-oxazolidinyl] methineacetamide:

Step 1: cis -3- (1,1-dimethylethoxycarbonylamino) -4-methylpyrrolidine

A solution of 1.5 g (5.2 mmol) of cis-1-phenylmethyl-3- (1,1-dimethylethoxycarbonylamino) -4-methylpyrrolidine (cf. US 4,753,953) in 50mL of methanol was treated with 200mg of Pd (OH) 2 / C followed by hydrogenation under 1 atmosphere of H2 for 3.5h. The mixture was filtered through celite, washing the filter cake with methanol. The filtrate was concentrated in vacuo to give a colorless oil, which was used directly in the next step. 1 H NMR (CD 3 OD) δ 4.85, 4.03, - 3.14, 3.05, 2.66, 2.45, 2.23, 1.46, 0.95.

Step 2: 3-Fluoro-1-nitro-4-rcis-3- (1,1-dimethylethoxycarbonylamino) -4-methylpyrrolidinylbenzene

A solution of the compound previously obtained and 1.8 g (10.3 mmol) of dibasic potassium phosphate in 40 mL of DMSO was heated at 90 ° C for 18 h. The mixture was cooled and diluted with 125mL of ethyl acetate followed by extraction with water (4 x 75mL). The organic layer was dried (Na2 SO4) and concentrated in vacuo to give 1.75 g of a yellow solid, pure enough for later use. MS (EI) m / z 339 (M +), 339, 282, 266, 223, 222, 208, 207, 154, 70, 57.

Step 3: 3-Fluoro-1-nitro-cis-3- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) -4-methylpyrrolidinylbenzene

A solution of 1.75g (5.17mmol) of the previous compound in 50mL of trifluoroacetic acid was stirred at room temperature for 18h. The solution was concentrated in vacuo and the obtained reddish brown oil was dissolved in ethyl acetate and extracted cautiously with saturated NaHC03 solution (4x). The combined aqueous layers were extracted with ethyl acetate and the combined organic layers were dried (Na2 SO4) and concentrated in vacuo. The residue was dissolved in 90mL of toluene and 45mL of dioxane and treated with 1.12g (12.7mmol) of Ν, Ν'-dimethylurea and 35mL of aqueous formaldehyde followed by heating under reflux for 2.5h. The mixture was cooled and concentrated in vacuo. The residue was chromatographed on 200g of 230-400 mesh silica gel, eluting with 1% (ν / ν) of methanol in chloroform. These procedures gave 3.65 g (86%) of the desired product as a yellow oily solid. MS (EI) m / z 351 (M +), 223.222,221,208,207, 182, 169, 154, 130, 113.

Step 4: 3-Fluoro-1- (phenylmethoxycarbonylamino) -cis-3- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yn-4-methylhydrolidinylbenzene

A solution of 1.82 g (5.17 mmol) in 200 mL of THF was treated with 750 mg of 10% palladium on carbon followed by hydrogenation under 45psi hydrogen pressure for 3h. The mixture was cooled to -20 ° C followed by addition of 30mL saturated NaHC03 solution. The mixture was then treated with 1.10 g (0.92 mL, 6.46 mmol) of benzyl chloroformate followed by warming to ambient temperature for 18 h. The mixture was filtered through celite, washing the filter cake with methanol and dichloromethane. The filtrate was concentrated in vacuo and the residue was dissolved in dichloromethane and extracted with water (3 x 30mL). Drying (Na2 SO4) and concentration in vacuo gave a purple foam which was chromatographed on 125 g of 230-300 mesh silica gel, eluting with 1-5% methanol in dichloromethane. These procedures gave 1.74 g (74%) of the title compound as a rigid foam. 1 HNMR (CDCl 3) δ 7.34, 6.92, 6.53, 5.18, 4.19, 4.13, 3.69, 3.58, 3.52, 3.41, 3.15, 2 , 86, 2.37, 1.05.

Step 5: (R) -3- (3-Fluoro-4- (cis-3- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) -4-methylpyrrolidinophenyl) -2- 5-oxazolidinylmethanol

A solution of 860mg (1.89mmol) of the previous compound in 25mL of THF at -78 ° C was treated with 1.3ml (2.08mmol) of n-butyllithium in hexane followed by heating to -50 ° C. After stirring at -50 ° C for 20 minutes, 286mg (0.28mL, 1.98mmol) of (R) - (-) - glycidylbutyrate was added. The mixture was warmed to 0 ° C for 30 minutes and then to at room temperature for 18h. The mixture was treated with saturated NH4 CI solution and diluted with ethyl acetate and then extracted with water (3x). The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (Na2 SO4) and concentrated in vacuo to give a brown oil. This material was chromatographed on 40g of 230-400 mesh silica gel, eluting with methanol in dichloromethane. These procedures gave 512mg (64%) of the title compound as a rigid foam. ¹H NMR (CDCl3) δ 7.35, 7.03, 6.60, 4.72, 4.22, 4.14, 3.94, 3.75, 3.70, 3.60, 3.54, 3.43, 3.18, 2.87, 2.39, 1.05. 67 ΕΡ Ο 788 498 / ΡΤ

Step 6: (R) - (3- (3-Fluoro-4- (cis-3- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) -4-methylpyrrolidinophenyl) -2-oxo-5-oxazolidinyl) methanesulfonyloxymethane

A solution of 1g (2.37 mmol) of the previous compound and 480mg (0.66mL, 4.74mmol) of triethylamine in 15mL of dichloromethane at 0 ° C was treated with 407mg (0.28mL, 3.56mmol) of methanesulfonyl chloride . The solution was stirred at 0 ° C for 1.5h, followed by heating, dilution with dichloromethane and extraction with water (3x). The organic layer was dried (Na2 SO4) and concentrated in vacuo to give the title compound. 1 H NMR (CDCl 3) δ 7.45, 7.02, 6.92, 4.92, 4.50 (1 H), 4.43, 4.23,4.17, 3.91,3.83, 3.65, 3.50, 3.29, 3.11, 2.89, 2.48, 1.12.

The title compound was prepared according to the procedure described in Example 1, Step 7: (SWN1 - ((3-Fluoro-4- (cis -3- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl-4-methylpyrrolidinophenyl) 5-oxazolidinyl) methylacetamide

A solution of the above mesylate in 6 mL of THF and 6 mL of isopropyl alcohol was treated with 6 mL of concentrated ammonium hydroxide. The mixture was heated at 100 ° C in a sealed tube for 48h. The mixture was cooled and diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate (2x). The mixture was treated with saturated NaCl solution and then extracted with chloroform (3x). The combined organic layers were dried (Na2 SO4) and concentrated in vacuo. The residue was dissolved in 15mL of pyridine and cooled to 0 ° C. The solution was treated with 0.5mL of acetic anhydride, followed by warming to room temperature for 20h. The mixture was concentrated in vacuo and the residue was chromatographed on 75g of 230-400 mesh silica gel eluting with methanol in dichloromethane. These procedures gave 934mg (85%) of the title compound as a white, hard foam. MS (FAB) m / z 463 (M + H), 464, 463, 462, 461, 364, 363, 361, 333, 101.44.

Step 8: (SHN) - ((3-Fluoro-4- (cis-3-amino-4-methylpyrrolidinyl) phenyl) -2-oxo-5-oxazolidinyl) methylacetamide

A solution of 875mg (1.89mmol) of the previous compound in 5ml of 2N HCl solution was stirred at room temperature for 20h. The solution was concentrated in vacuo, and the residue was azeotroped with toluene. These procedures yielded 662mg (ca. 100%) of the title compound as a rigid amber foam. MS (FAB) m / z 351 (M + H), 427, 352, 351, 350, 349, 255, 68 Ρ 788 498 / ΡΤ 123, 101, 89, 44. HRMS (FAB) calc. Calc'd for C 21 H 18 F 3 N 4 O 3 + H, 351.1832, found 351.1840.

Step 9: (S) -N- [3-Fluoro-4- (cis-3- (methoxycarbonylamino) -4-methyl-pyrrolidinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A solution of 150mg (0.43mmol) of the previous compound in 6mL of acetone and 3mL of water was treated with 108mg (1.29mmol) of NaHC03 and cooled to 0 ° C. The solution was then treated with 89mg (73μΙ, 0.95mmol) of methyl chloroformate. The solution was then diluted with ethyl acetate and extracted with water (3x). Drying (Na 2 SO 4) and concentration in vacuo afforded a white solid, which was subjected to radial chromatography on a 2mm chromatotron plate, eluting with methanol in dichloromethane. These procedures gave 155mg (53%) of the title compound as a white solid. MS (EI) m / z 408 (M +), 409, 408, 364, 334, 333, 318, 289, 276, 215, 56. EXAMPLE 15 (S) -N- (3-Fluoro-4-cis-3- (hydroxyacetylamino) methyl-2-oxo-5-oxazolidinyl] methineacetamide.

Step 1: (S) -N- [3-Fluoro-4- (cis-3- (phenylmethoxyacetylamino) -4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A solution of 300mg (0.90mmol) of the amine (Example 14, Step 8) in 14mL of acetone and 7mL of water was treated with 302mg (3.60mmol) of NaHCO3 and cooled to 0 ° C. The solution was then treated with benzyloxyacetyl chloride (414mg, 0.35mL, 2.25mmol), followed by heating to ambient temperature for 72h. The mixture was diluted with ethyl acetate and water and the organic layer was extracted with water (3x). The organic layer was dried (Na2 SO4) and concentrated in vacuo to give a brown oil. This material was chromatographed on 30g of 230-400 mesh silica gel, eluting with methanol in dichloromethane. These procedures gave 132 mg (30%) of the title compound as a white solid. 1 H NMR (CDCl 3) δ 7.57, 7.36, 7.03, 5.98, 4.77, 4.67, 4.63, 4.04, 3.74, 3.70, 3.63, 3.55, 3.45, 3.38, 2.71,23, 1.07.

87 111 ΕΡ Ο 788 498 / ΡΤ 69

Step 2: (S) -N- (3-Fluoro-4- (cis-3- (hydroxyacetylamino) -4-methylpyrrolidinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A solution of 107mg (0.21 mmol) of the previous compound in 25mL of methanol was treated with 100mg of 10% palladium on carbon followed by hydrogenation at one atmosphere for 72h. The mixture was filtered through celite, and the filtrate was concentrated under vacuum. The residue was subjected to radial chromatography on a 2mm chromatotron plate, eluting with methanol in dichloromethane. These procedures gave 24 mg (8%) of the title compound as a light beige solid. MS (EI) m / z 408 (M +), 408, 334, 333, 318, 289, 215, 70, 57, 56, 55. EXAMPLE 16 (S) -N- [ 3-methanesulfonylamino-4-methylpyrrolidinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A slurry of 200mg (0.57mmol) of the amine (Example 14, Step 8) in 10ml of dichloromethane was treated with 144mg (0.20ml, 1.43mmol) of triethylamine followed by cooling of the resulting solution to 0øC. The mixture was treated with 83mg (56pL, 0.73mmol) methanesulfonyl chloride, followed by warming to room temperature for 18h. The mixture was diluted with 50mL of ethyl acetate followed by extraction with water (3 x 30mL). The organic layer was dried (Na 2 SO 4) and concentrated in vacuo to give a white, off-white solid, which was subjected to radial chromatography on a 2mm chromatotron plate, eluting with methanol in dichloromethane. These procedures provided 11 mg (45%) of the title compound as a white solid. MS (EI) m / z 428 (M +), 429, 428, 384, 300, 280, 238, 236, 177, 70, 56.

R3 R4

OR14 6

R4 0

N

To

H

OH 7 71 R7 111 ΕΡ Ο 788 498 / ΡΤ

SCHEME II

12 72 87 111 ΕΡ Ο 788 498 / ΡΤ

SCHEME III

ΗΙ 87 111 ΕΡ Ο 788 498 / ΡΤ 73

SCHEME IV

Ο R3

R 21 (R = H, C 1 -C 2 alkyl) 17-21 R 3

NH · HCl R 22

75 87 111 ΕΡ Ο 788 498 / ΡΤ

SCHEME VI

76 87 111 ΕΡ Ο 788 498 / ΡΤ

SCHEME VII

87 111 ΕΡ Ο 788 498 / ΡΤ 77

SCHEME XI

R 0 is 0 or R 2 is hydrogen or

Ph

N ', R 3', -O-R 3 ', R 3'

Ph A »

78 87 111 ΕΡ Ο 788 498 / ΡΤ

SCHEME XII

22 87 111 ΕΡ Ο 788 498 / ΡΤ 80

SCHEME XIV

SCHEME XV

27 2 >

82 87 111 ΕΡ Ο 788 498 / ΡΤ

SCHEME XVII

83 87 111 ΕΡ Ο 788 498 / ΡΤ

SCHEME XVIII

87

Lisbon, .14

By PHARMACIA & UPJOHN COMPANY - THE OFFICIAL AGENT -

tni " ANTÓNIO JOÃO DA CUNHA FERREIRA

Ag. Of. Pr. Lnd.

Rua das Flores, 74-4-. i Ό00-195 LISBON [

Claims (10)

87 111 498 498 / ΡΤ 1/5 Claims 1. Compound of Structural Formula I: or pharmaceutically acceptable salts thereof, wherein: Q is selected from structures i, ii, iii, iv and v: (a) H or F, (b) OR7, (c) SR7, (d) NR8 R9, ) CN, (f) C alco alco alco alkoxycarbonyl, (g) carboxamide, (H) C 1 -C 4 acyl optionally substituted with one or more of the following: fluorine, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 acyloxy; (i) NHO (C1 -C6 alkyl) or NHOCH2 Ph (j) NS02 R where R is C1-4 alkyl optionally substituted with one or more F, Cl, alkoxy or phenyl; each of R2 is independently selected from the others from (a) H or F, (b) OH, (c) OR wherein R is C1 -C6 alkyl, (d) C1 -C4 alkyl, (e) Ph; each of R3 is independently selected from the others from (a) H, (b) C1 -C3 alkyl which may be optionally substituted with F, Cl, hydroxy, C1 -C3 alkoxycarbonyl, C1 -C3 acyloxy, C1 -C3 alkyloxy or N (C1 -C4 alkyl) 2, ( c) phenyl, (d) pyridyl; R4 are independently H, OCH3, F or Cl; R 5 is (a) hydrogen, (b) C 1 -C 8 alkyl optionally substituted with one or more of the following: F, Cl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 acyloxy, (c) C 3 -C 6 cycloalkyl, d) amino, (e) C1 -C8 alkylamino, (f) C1 -C8 dialkylamino, (g) C1 -C8 alkoxy; R6 is (a) O, (b) S, (c) NR10, (d) CR11 R12, (e) (OR) 2, wherein R = C1 -C6 alkyl, (f) O (CH2) m O, (I) to fill the valence OH and Η, H and Η, H and F or F and Η, H and Η, H and Η H and F H and F H Η Ο Ο Ο ΡΤ ΡΤ ΡΤ ΡΤ ΡΤ ΡΤ ΡΤ ΡΤ ΡΤ ΡΤ ΡΤ ΡΤ ΡΤ ΡΤ ΡΤ e e F; R7 is (a) H, (b) C1 -C6 alkyl optionally substituted with one or more of the following: F, Cl, -CN, hydroxy, C1 -C6 alkoxy, C1 -C6 acyloxy, C1 -C6 alkoxycarbonyl, phenyl, (c) , -Co is optionally substituted with one or more of the following: hydroxy, C1-6 alkoxy, C1-6 acyloxy, (d) C1 -C8 alkoxycarbonyl, (e) carboxamide, optionally substituted with a C1 -C4 alkyl or phenyl at the carboxamide nitrogen, (f) phenyl, optionally substituted with one or more of the following: halogen, CN, C1 -C6 alkoxy, C1 -C6 alkoxycarbonyl, alkyl optionally substituted with one or more of F or C 1 -C 6 alkoxy, R 8 and R 9 are independently selected from: (a) H, (b) C 1 -C 8 alkyl optionally substituted with one or more of the following: Cl, -CN, hydroxy, C 1 -C 8 alkoxy, C 1 -C 8 acyloxy, C 1 -C 6 alkoxycarbonyl, phenyl, (c) C 1 -C 6 acyl optionally substituted with one or more of the following: hydroxy, C 1 -C 6 alkoxy, (D) benzoyl optionally substituted with one or more of the following: F, Cl, hydroxy, C1 -C8 alkoxy, C1 -C6 acyloxy, amino, C1 -C4 acylamino, C1 -C4 alkoxycarbonylamino, C1 -C4 alkoxycarbonylamino, , (e) C1 -C6 alkoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, (f) carboxamide, optionally substituted by C1 -C4 alkyl or phenyl (g) trifluoroacetyl, (h) CO (C 1 -C 6 alkyl); R10 is (a) H, (b) OR7, (c) NHR7, (d) C1 -C6 alkyl optionally substituted with phenyl; The other is R11 and R12 are independently selected from: (a) H, F, (b) C1 -C4 alkyl optionally substituted with halogen, hydroxy, C1 -C4 alkoxy, C 1 -C 4 alkoxycarbonyl, phenyl, (c) C 1 -C 6 acyl, (d) C 1 -C 4 alkoxycarbonyl, (e) CN; R17 is (a) O, (b) S; R18 and R19 are independently selected from: (a) H, (b) C1 -C4 alkyl optionally substituted with halogen, hydroxy, C1 -C4 alkoxy (c) OH, (d) alkoxy optionally substituted with hydroxy or C1-4 alkoxy (e) NR8R1, (f) -OC (O) C1 -C20 alkyl, R20 is (a) H, (b) CH3; n is 0 or 1 and m is 2 or 3. The compound of claim 1 wherein Q is structure (i). The compound of claim 1 in which Q is structure (ii). The compound of claim 1 in which Q is structure (iii). The compound of claim 1 wherein Q is structure (iv). The compound of claim 1 wherein Q is structure (v). The compound of claim 1 in which each R 4 is fluoro. The compound of claim 1 in which one of R4 is fluoro and hydrogen. The compound of claim 1 in which R 5 is hydrogen, methoxy or methyl J 87 111 490 498 / ΡΤ 5/5 The compound of claim 1 in which R 6 is oxygen, OCH 2 CH 2, HOH or NOCH 3. Use of a compound of Formula I of claim 1 for the preparation of a medicament useful in the treatment of microbial infections in warm-blooded animals, including humans, by administering to a patient a pharmaceutically effective amount of the compound. By PHARMACIA & UPJOHN COMPANY - THE OFFICIAL AGENT -